curcumin and Alzheimer-Disease

Aberrant neurogenesis is a major factor in psychiatric and neurological disorders that have significantly attracted the attention of neuroscientists. Curcumin is a primary constituent of curcuminoid that exerts several positive pharmacological effects on aberrant neurogenesis. First, it is important to understand the different processes of neurogenesis, and whether their dysfunction promotes etiology as well as the development of many psychiatric and neurological disorders; then investigate mechanisms by which curcumin affects neurogenesis as an active participant in pathophysiological events. Based on scientometric studies and additional extensive research, we explore the mechanisms by which curcumin regulates adult neurogenesis and in turn affects psychiatric diseases, i.e., depression and neurological disorders among them traumatic brain injury (TBI), stroke, Alzheimer's disease (AD), Gulf War Illness (GWI) and Fragile X syndrome (FXS). This review aims to elucidate the therapeutic effects and mechanisms of curcumin on adult neurogenesis in various psychiatric and neurological disorders. Specifically, we discuss the regulatory role of curcumin in different activities of neural stem cells (NSCs), including proliferation, differentiation, and migration of NSCs. This is geared toward providing novel application prospects of curcumin in treating psychiatric and neurological disorders by regulating adult neurogenesis.

Topics: Adult; Alzheimer Disease; Cell Differentiation; Curcumin; Humans; Nervous System Diseases; Neurogenesis

Topics: Aged; Alzheimer Disease; Biological Availability; Curcumin; Humans; Neurodegenerative Diseases

The retina is a key focus in the search for biomarkers of Alzheimer's disease (AD) because of its accessibility and shared development with the brain. The pathological hallmarks of AD, amyloid beta (Aβ), and hyperphosphorylated tau (pTau) have been identified in the retina, although histopathologic findings have been mixed. Several imaging-based approaches have been developed to detect retinal AD pathology in vivo. Here, we review the research related to imaging AD-related pathology in the retina and implications for future biomarker research.. Electronic searches of published literature were conducted using PubMed and Google Scholar.. Curcumin fluorescence and hyperspectral imaging are both promising methods for detecting retinal Aβ, although both require validation in larger cohorts. Challenges remain in distinguishing curcumin-labeled Aβ from background fluorescence and standardization of dosing and quantification methods. Hyperspectral imaging is limited by confounding signals from other retinal features and variability in reflectance spectra between individuals. To date, evidence of tau aggregation in the retina is limited to histopathologic studies. New avenues of research are on the horizon, including near-infrared fluorescence imaging, novel Aβ labeling techniques, and small molecule retinal tau tracers. Artificial intelligence (AI) approaches, including machine learning models and deep learning-based image analysis, are active areas of investigation.. Although the histopathological evidence seems promising, methods for imaging retinal Aβ require further validation, and in vivo imaging of retinal tau remains elusive. AI approaches may hold the greatest promise for the discovery of a characteristic retinal imaging profile of AD. Elucidating the role of Aβ and pTau in the retina will provide key insights into the complex processes involved in aging and in neurodegenerative disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Artificial Intelligence; Biomarkers; Curcumin; Humans; Neurodegenerative Diseases; Retina

For thousands of years, mankind has been using plant extracts or plants themselves as medicinal herbs. Currently, there is a great deal of public interest in naturally occurring medicinal substances that are virtually non-toxic, readily available, and have an impact on well-being and health. It has been noted that dietary curcumin is one of the regulators that may positively influence changes in the brain after ischemia. Curcumin is a natural polyphenolic compound with pleiotropic biological properties. The observed death of pyramidal neurons in the CA1 region of the hippocampus and its atrophy are considered to be typical changes for post-ischemic brain neurodegeneration and for Alzheimer's disease. Additionally, it has been shown that one of the potential mechanisms of severe neuronal death is the accumulation of neurotoxic amyloid and dysfunctional tau protein after cerebral ischemia. Post-ischemic studies of human and animal brains have shown the presence of amyloid plaques and neurofibrillary tangles. The significant therapeutic feature of curcumin is that it can affect the aging-related cellular proteins, i.e., amyloid and tau protein, preventing their aggregation and insolubility after ischemia. Curcumin also decreases the neurotoxicity of amyloid and tau protein by affecting their structure. Studies in animal models of cerebral ischemia have shown that curcumin reduces infarct volume, brain edema, blood-brain barrier permeability, apoptosis, neuroinflammation, glutamate neurotoxicity, inhibits autophagy and oxidative stress, and improves neurological and behavioral deficits. The available data suggest that curcumin may be a new therapeutic substance in both regenerative medicine and the treatment of neurodegenerative disorders such as post-ischemic neurodegeneration.

Topics: Alzheimer Disease; Amyloid; Animals; Apoptosis; Atrophy; Biological Availability; Blood-Brain Barrier; Brain Edema; Brain Ischemia; Curcumin; Disease Models, Animal; Gastrointestinal Microbiome; Gerbillinae; Hippocampus; Humans; Mice; Neuroinflammatory Diseases; Neuroprotective Agents; Oxidative Stress; Rats; tau Proteins

Sleep disturbances, as well as sleep-wake rhythm disorders, are characteristic symptoms of Alzheimer's disease (AD) that may head the other clinical signs of this neurodegenerative disease. Age-related structural and physiological changes in the brain lead to changes in sleep patterns. Conditions such as AD affect the cerebral cortex, basal forebrain, locus coeruleus, and the hypothalamus, thus changing the sleep-wake cycle. Sleep disorders likewise adversely affect the course of the disease. Since the sleep quality is important for the proper functioning of the memory, impaired sleep is associated with problems in the related areas of the brain that play a key role in learning and memory functions. In addition to synthetic drugs, utilization of medicinal plants has become popular in the treatment of neurological diseases. Curcuminoids, which are in a diarylheptanoid structure, are the main components of turmeric. Amongst them, curcumin has multiple applications in treatment regimens of various diseases such as cardiovascular diseases, obesity, cancer, inflammatory diseases, and aging. Besides, curcumin has been reported to be effective in different types of neurodegenerative diseases. Scientific studies exclusively showed that curcumin leads significant improvements in the pathological process of AD. Yet, its low solubility hence low bioavailability is the main therapeutic limitation of curcumin. Although previous studies have focused different types of advanced nanoformulations of curcumin, new approaches are needed to solve the solubility problem. This review summarizes the available scientific data, as reported by the most recent studies describing the utilization of curcumin in the treatment of AD and sleep deprivation-related consequences.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Curcumin; Female; Humans; Male; Middle Aged; Prospective Studies; Sleep Deprivation

Prof. Dr. Peter Riederer, the former Head of the Neurochemistry Department of the Psychiatry and Psychotherapy Clinic at the University of Würzburg (Germany), has been one of the pioneers of research into oxidative stress in Parkinson's and Alzheimer's disease (AD). This review will outline how his scientific contribution to the field has opened a new direction for AD treatment beyond "plaques and tangles". In the 1990s, Prof. Riederer was one of the first scientists who proposed oxidative stress and neuroinflammation as one of the major contributors to Alzheimer's disease, despite the overwhelming support for the "amyloid-only" hypothesis at the time, which postulated that the sole and only cause of AD is β-amyloid. His group also highlighted the role of advanced glycation end products, sugar and dicarbonyl-derived protein modifications, which crosslink proteins into insoluble aggregates and potent pro-inflammatory activators of microglia. For the treatment of chronic neuroinflammation, he and his group suggested that the most appropriate drug class would be cytokine-suppressive anti-inflammatory drugs (CSAIDs) which have a broader anti-inflammatory action range than conventional non-steroidal anti-inflammatory drugs. One of the most potent CSAIDs is curcumin, but it suffers from a variety of pharmacokinetic disadvantages including low bioavailability, which might have tainted many human clinical trials. Although a variety of oral formulations with increased bioavailability have been developed, curcumin's absorption after oral delivery is too low to reach therapeutic concentrations in the micromolar range in the systemic circulation and the brain. This review will conclude with evidence that rectally applied suppositories might be the best alternatives to oral medications, as this route will be able to evade first-pass metabolism in the liver and achieve high concentrations of curcumin in plasma and tissues, including the brain.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Anti-Inflammatory Agents; Curcumin; Cytokines; Humans; Neuroinflammatory Diseases

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, which is caused by multi-factors and characterized by two histopathological hallmarks: amyloid-β (Aβ) plaques and neurofibrillary tangles of Tau proteins. Thus, researchers have been devoting tremendous efforts to developing and designing new molecules for the early diagnosis of AD and curative purposes. Curcumin and its scaffold have fluorescent and photochemical properties. Mounting evidence showed that curcumin scaffold had neuroprotective effects on AD such as anti-amyloidogenic, anti-inflammatory, anti-oxidative and metal chelating. In this review, we summarized different curcumin derivatives and analyzed the in vitro and in vivo results in order to exhibit the applications in AD diagnosis, therapeutic monitoring and therapy. The analysis results showed that, although curcumin and its analogues have some disadvantages such as short wavelength and low bioavailability, these shortcomings can be conquered by modifying the structures. Curcumin scaffold still has the potential to be a multifunctional tool for AD research, including AD diagnosis and therapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Anti-Inflammatory Agents; Curcumin; Humans; Neurofibrillary Tangles; Plaque, Amyloid; tau Proteins

Curcumin is the most important active component in turmeric extracts. Curcumin, a natural monomer from plants has received a considerable attention as a dietary supplement, exhibiting evident activity in a wide range of human pathological conditions. In general, curcumin is beneficial to human health, demonstrating pharmacological activities of anti-inflammation and antioxidation, as well as antitumor and immune regulation activities. Curcumin also presents therapeutic potential in neurodegenerative, cardiovascular and cerebrovascular diseases. In this review article, we summarize the advancements made in recent years with respect to curcumin as a biologically active agent in malignant tumors, Alzheimer's disease (AD), hematological diseases and viral infectious diseases. We also focus on problems associated with curcumin from basic research to clinical translation, such as its low solubility, leading to poor bioavailability, as well as the controversy surrounding the association between curcumin purity and effect. Through a review and summary of the clinical research on curcumin and case reports of adverse effects, we found that the clinical transformation of curcumin is not successful, and excessive intake of curcumin may have adverse effects on the kidneys, heart, liver, blood and immune system, which leads us to warn that curcumin has a long way to go from basic research to application transformation.

Topics: Alzheimer Disease; Anti-Inflammatory Agents; Antioxidants; Biological Availability; Curcumin; Humans

Alzheimer's disease (AD) is a complex neurodegenerative disorder that affects multiple brain regions and is difficult to treat. In this study we used 22 AD large-scale gene expression datasets to identify a consistent underlying portrait of AD gene expression across multiple brain regions. Then we used the portrait as a platform for identifying treatments that could reverse AD dysregulated expression patterns. Enrichment of dysregulated AD genes included multiple processes, ranging from cell adhesion to CNS development. The three most dysregulated genes in the AD portrait were the inositol trisphosphate kinase, ITPKB (upregulated), the astrocyte specific intermediate filament protein, GFAP (upregulated), and the rho GTPase, RHOQ (upregulated). 41 of the top AD dysregulated genes were also identified in a recent human AD GWAS study, including PNOC, C4B, and BCL11A. 42 transcription factors were identified that were both dysregulated in AD and that in turn affect expression of other AD dysregulated genes. Male and female AD portraits were highly congruent. Out of over 250 treatments, three datasets for exercise or activity were identified as the top three theoretical treatments for AD via reversal of large-scale gene expression patterns. Exercise reversed expression patterns of hundreds of AD genes across multiple categories, including cytoskeleton, blood vessel development, mitochondrion, and interferon-stimulated related genes. Exercise also ranked as the best treatment across a majority of individual region-specific AD datasets and meta-analysis AD datasets. Fluoxetine also scored well and a theoretical combination of fluoxetine and exercise reversed 549 AD genes. Other positive treatments included curcumin. Comparisons of the AD portrait to a recent depression portrait revealed a high congruence of downregulated genes in both. Together, the AD portrait provides a new platform for understanding AD and identifying potential treatments for AD.

Topics: Alzheimer Disease; Curcumin; Female; Fluoxetine; Gene Expression; Humans; Inositol; Interferons; Male; rho GTP-Binding Proteins; Transcription Factors

Progressive degeneration and dysfunction of the nervous system because of oxidative stress, aggregations of misfolded proteins, and neuroinflammation are the key pathological features of neurodegenerative diseases. Alzheimer's disease is a chronic neurodegenerative disorder driven by uncontrolled extracellular deposition of β-amyloid (Aβ) in the amyloid plaques and intracellular accumulation of hyperphosphorylated tau protein. Curcumin is a hydrophobic polyphenol with noticeable neuroprotective and anti-inflammatory effects that can cross the blood-brain barrier. Therefore, it is widely studied for the alleviation of inflammatory and neurological disorders. However, the clinical application of curcumin is limited due to its low aqueous solubility and bioavailability. Recently, nano-based curcumin delivery systems are developed to overcome these limitations effectively. This review article discusses the effects and potential mechanisms of curcumin-loaded PLGA nanoparticles in Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Curcumin; Humans; Neuroprotective Agents; Plaque, Amyloid

Alzheimer's disease (AD) is one of the most common types of dementia, especially in elderly, with an increasing number of people suffering from this disease worldwide. There are no available disease-modifying therapies and only four drugs are approved for the relief of symptoms. Currently, the therapeutic approach used for AD treatment is based on single target drugs, which are not capable to stop its progression. To address this issue, multi-target compounds, combining two or more pharmacophores in a single molecular entity, have gained increasing interest to deal with the multiple factors related to AD. The exact cause of AD is not yet completely disclosed, and several hallmarks have been associated to this neurodegenerative disease. Even though, the accumulation of both amyloid-β plaques (Aβ) and neurofibrillary tangles (NFTs) are fully accepted as the main AD hallmarks, being object of lots of research for early-stage diagnosis and pharmacological therapy. In this context, this review summarizes the state-of-the-art in the field of dual-target inhibitors of both Aβ and tau aggregation simultaneously, including the design and synthetic strategy of the dual-target compounds, as well as a brief structure-activity relationships (SAR) analysis.

Topics: Alzheimer Disease; Aminoquinolines; Amyloid beta-Peptides; Curcumin; Heterocyclic Compounds, 4 or More Rings; Humans; Molecular Structure; Structure-Activity Relationship; Tacrine; tau Proteins

Alzheimer's disease (AD) is the most common form of dementia characterized by presence of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of tau protein. Currently there are close to 50 million people living with dementia and this figure is expected to increase to 75 million by 2030 putting a huge burden on the economy due to the health care cost. Considering the effects on quality of life of patients and the increasing burden on the economy, there is an enormous need of new disease modifying therapies to tackle this disease. The current therapies are dominated by only symptomatic treatments including cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers but no disease modifying treatments exist so far. After several failed attempts to develop drugs against amyloidopathy, tau targeting approaches have been in the main focus of drug development against AD. After an overview of the tauopathy in AD, this review summarizes recent findings on the development of small molecules as therapeutics targeting tau modification, aggregation, and degradation, and tau-oriented multi-target directed ligands. Overall, this work aims to provide a comprehensive and critical overview of small molecules which are being explored as a lead candidate for discovering drugs against tauopathy in AD.

Topics: Alzheimer Disease; Animals; Benzodioxoles; Cholinesterase Inhibitors; Cholinesterases; Curcumin; Humans; Molecular Targeted Therapy; Neurofibrillary Tangles; Neuroprotective Agents; Phosphorylation; Plaque, Amyloid; Protein Aggregation, Pathological; Protein Processing, Post-Translational; Quinazolines; Receptors, N-Methyl-D-Aspartate; tau Proteins; Thiadiazoles

Amyloidosis is a concept that implicates disorders and complications that are due to abnormal protein accumulation in different cells and tissues. Protein aggregation-associated diseases are classified according to the type of aggregates and deposition sites, such as neurodegenerative disorders and type 2 diabetes mellitus. Polyphenolic phytochemicals such as curcumin and its derivatives have anti-amyloid effects both in vitro and in animal models; however, the underlying mechanisms are not understood. In this review, we summarized possible mechanisms by which curcumin could interfere with self-assembly processes and reduce amyloid aggregation in amyloidosis. Furthermore, we discuss clinical trials in which curcumin is used as a therapeutic agent for the treatment of diseases linking to protein aggregates.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Clinical Trials as Topic; Creutzfeldt-Jakob Syndrome; Curcumin; Diabetes Mellitus, Type 2; Humans; Huntington Disease; Hypoglycemic Agents; Mitochondria; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Protein Aggregates; tau Proteins

Curcumin, an active component of the rhizome turmeric, has gained much attention as a plant-based compound with pleiotropic pharmacological properties. It possesses anti-inflammatory, antioxidant, hypoglycemic, antimicrobial, neuroprotective, and immunomodulatory activities. However, the health-promoting utility of curcumin is constrained due to its hydrophobic nature, water insolubility, poor bioavailability, rapid metabolism, and systemic elimination. Therefore, an innovative stride was taken, and complexes of metals with curcumin have been synthesized. Curcumin usually reacts with metals through the β-diketone moiety to generate metal-curcumin complexes. It is well established that curcumin strongly chelates several metal ions, including boron, cobalt, copper, gallium, gadolinium, gold, lanthanum, manganese, nickel, iron, palladium, platinum, ruthenium, silver, vanadium, and zinc. In this review, the pharmacological, chemopreventive, and therapeutic activities of metal-curcumin complexes are discussed. Metal-curcumin complexes increase the solubility, cellular uptake, and bioavailability and improve the antioxidant, anti-inflammatory, antimicrobial, and antiviral effects of curcumin. Metal-curcumin complexes have also demonstrated efficacy against various chronic diseases, including cancer, arthritis, osteoporosis, and neurological disorders such as Alzheimer's disease. These biological activities of metal-curcumin complexes were associated with the modulation of inflammatory mediators, transcription factors, protein kinases, antiapoptotic proteins, lipid peroxidation, and antioxidant enzymes. In addition, metal-curcumin complexes have shown usefulness in biological imaging and radioimaging. The future use of metal-curcumin complexes may represent a new approach in the prevention and treatment of chronic diseases.

Topics: Alzheimer Disease; Animals; Arthritis; Coordination Complexes; Curcumin; Humans; Nervous System Diseases; Osteoporosis

Alzheimer's disease (AD) is the most prevalent dementia in the elderly, causing disability, physical, psychological, social, and economic damage to the individual, their families, and caregivers. Studies have shown some spices, such as saffron, rosemary, cinnamon, turmeric, and ginger, have antioxidant and anti-inflammatory properties that act in inhibiting the aggregation of acetylcholinesterase and amyloid in AD. For this reason, spices have been studied as beneficial sources against neurodegenerative diseases, including AD. In this sense, this study aims to present a review of some spices (Saffron, Rosemary, Cinnamon, Turmeric and Ginger) and their bioactive compounds, most consumed and investigated in the world regarding AD. In this article, scientific evidence is compiled in clinical trials in adults, the elderly, animals, and in vitro, on properties considered neuroprotective, having no or negative effects on neuroprotection of these spices and their bioactive compounds. The importance of this issue is based on the pharmacological treatment for AD that is still not very effective. In addition, the recommendations and prescriptions of these spices are still permeated by questioning and lack of robust evidence of their effects on neurodegeneration. The literature search suggests all spices included in this article have bioactive compounds with anti-inflammatory and antioxidant actions associated with neuroprotection. To date, the amounts of spice ingestion in humans are not uniform, and there is no consensus on its indication and chronic consumption guarantees safety and efficacy in neuroprotection. Therefore, clinical evidence on this topic is necessary to become a formal adjuvant treatment for AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Biological Products; Cinnamomum zeylanicum; Crocus; Curcuma; Humans; Neuroprotection; Plant Extracts; Rosmarinus; Spices; Zingiber officinale

Curcumin, isolated from the rhizome of Curcuma longa, is one of the most extensively studied phytochemicals. This natural compound has a variety of pharmacological effects including antioxidant, anti-inflammatory, anti-tumor, cardio-protective, hepato-protective and anti-diabetic. Wnt signaling pathway, one of the potential targets of curcumin through upregulation and/or downregulation, plays a significant role in many diseases, even in embryogenesis and development of various organs and systems. In order to exert an anti-tumor activity in the organism, curcumin seems to inhibit the Wnt pathway. The downstream mediators of Wnt signaling pathway such as c-Myc and cyclin D1 are also modified by curcumin. This review demonstrates how curcumin influences the Wnt signaling pathway and is beneficial for the treatment of neurological disorders (Alzheimer's and Parkinson's diseases), cancers (melanoma, lung cancer, breast cancer, colon cancer, endothelial carcinoma, gastric carcinoma and hepatocellular carcinoma) and other diseases, such as diabetes mellitus or bone disorders.

Topics: Alzheimer Disease; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Curcuma; Curcumin; Humans; Neoplasms; Neuroprotective Agents; Parkinson Disease; Wnt Signaling Pathway

Worldwide, Alzheimer's disease (AD) is the most common neurodegenerative multifactorial disease influencing the elderly population. Nowadays, several medications, among them curcumin, are used in the treatment of AD. Curcumin, which is the principal component of

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Curcumin; Drug Development; Humans; Neuroprotective Agents; Protein Binding

Topics: Alzheimer Disease; Animals; Curcuma; Curcumin; Disease Models, Animal; Heart Diseases; Humans; Liver Diseases; Lung Neoplasms; Medicine, Ayurvedic; Osteoarthritis; Phytotherapy

It is estimated that over 44 million people across the globe have dementia, and half of these cases are believed to be Alzheimer's disease (AD). As the proportion of the global population which is over the age 60 increases so will the number of individuals living with AD. This will result in ever-increasing demands on healthcare systems and the economy. AD can be either sporadic or familial, but both present with similar pathobiology and symptoms. Three prominent theories about the cause of AD are the amyloid, tau and mitochondrial hypotheses. The mitochondrial hypothesis focuses on mitochondrial dysfunction in AD, however little attention has been given to the potential dysfunction of the mitochondrial ATP synthase in AD. ATP synthase is a proton pump which harnesses the chemical potential energy of the proton gradient across the inner mitochondrial membrane (IMM), generated by the electron transport chain (ETC), in order to produce the cellular energy currency ATP. This review presents the evidence accumulated so far that demonstrates dysfunction of ATP synthase in AD, before highlighting two potential pharmacological interventions which may modulate ATP synthase.

Topics: Alzheimer Disease; Animals; Benzofurans; Brain; Curcumin; Energy Metabolism; Humans; Mitochondria; Mitochondrial Proton-Translocating ATPases; Neuroprotective Agents

Alzheimer's disease (AD) is increasingly prevalent and over 99% of drugs developed for AD have failed in clinical trials. A growing body of literature suggests that potent inhibitors of tumor necrosis factor-α (TNF-α) have potential to improve cognitive performance.. In this review, we summarize the evidence regarding the potential for TNF-α inhibition to prevent AD and improve cognitive function in people at risk for dementia.. We conducted a literature review in PubMed, screening all articles published before July 7, 2019 related to TNF blocking agents and curcumin (another TNF-α inhibitor) in the context of AD pathology. The keywords in the search included: AD, dementia, memory, cognition, TNF-α, TNF inhibitors, etanercept, infliximab, adalimumab, golimumab, and curcumin.. Three large epidemiology studies reported etanercept treated patients had 60 to 70% lower odds ratio (OR) of developing AD. Two small-randomized control trials (RCTs) demonstrated an improvement in cognitive performance for AD patients treated with etanercept. Studies using animal models of dementia also reported similar findings with TNF blocking agents (etanercept, infliximab, adalimumab, Theracurmin), which appeared to improve cognition. A small human RCT using Theracurmin, a well-absorbed form of curcumin that lowers TNF-α, showed enhanced cognitive performance and decreased brain levels of amyloid-β plaque and tau tangles.. TNF-α targeted therapy is a biologically plausible approach to the preservation of cognition, and warrants larger prospective RCTs to further investigate potential benefits in populations at risk of developing AD.

Topics: Adalimumab; Alzheimer Disease; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Curcumin; Etanercept; Humans; Tumor Necrosis Factor-alpha

Curcumin is a polyphenolic natural compound with diverse and attractive biological properties, which may prevent or ameliorate pathological processes underlying age-related cognitive decline, Alzheimer's disease (AD), dementia, or mode disorders. AD is a chronic neurodegenerative disorder that is known as one of the rapidly growing diseases, especially in the elderly population. Moreover, being the eminent cause of dementia, posing problems for families, societies as well a severe burden on the economy. There are no effective drugs to cure AD. Although curcumin and its derivatives have shown properties that can be considered useful in inhibiting the hallmarks of AD, however, they have low bioavailability. Furthermore, to combat diagnostic and therapeutic limitations, various nanoformulations have also been recognized as theranostic agents that can also enhance the pharmacokinetic properties of curcumin and other bioactive compounds. Nanocarriers have shown beneficial properties to deliver curcumin and other nutritional compounds against the blood-brain barrier to efficiently distribute them in the brain. This review spotlights the role and effectiveness of curcumin and its derivatives in AD. Besides, the gut metabolism of curcumin and the effects of nanoparticles and their possible activity as diagnostic and therapeutic agents in AD also discussed.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Biological Availability; Blood-Brain Barrier; Curcumin; Drug Delivery Systems; Humans; Nanostructures; Nanotechnology; tau Proteins

Alzheimer's disease (AD) is a well known neurodegenerative disorder alarming millions of people worldwide and the subsequent epidemiological statistics highlights the implication of the disease. AD is a multi-factorial disease, a variety of single-target directed drugs that have reached clinical trials have unsuccessful. Hence, various factors associated without set of AD have been considered in targeted drug discovery and development. Triazoles are five-membered heterocyclic scaffold due to their broad range of biological activities. The present review focuses on the recent developments in the area of medicinal chemistry to explore the diverse chemical structures of potential inhibitors of Alzheimer's disease and also look at its structure-activity relationships (SAR) studies of bioactive compounds for future discovery of suitable drug candidates. The prominence has been given on the major advancements in the medicinal brochure of this pharmacophore for the period during 2012-2019.

Topics: Acetylcholinesterase; Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Molecular Structure; Neuroprotective Agents; Structure-Activity Relationship; Triazoles

Alzheimer's disease constitutes a growing cause of cognitive impairment in aging population. Given that current treatments do not produce the desired therapeutic effects, the need for finding alternative biological and pharmacological approaches is critical. Accumulating evidence suggests inflammatory and oxidative stress responses as potential causal factors of cognitive impairments in Alzheimer's disease and healthy aging. Curcumin has received increased interest due to its unique molecular structure that targets inflammatory and antioxidant pathways as well as (directly) amyloid aggregation; one of the major hallmarks of Alzheimer's disease. Therefore, this review summarizes preclinical and clinical findings on curcumin as a potential cognitive enhancer in Alzheimer's disease and normal aging. Databases used for literature searches include PubMed, EMBASE and Web of Science; in addition, clinicaltrials.gov was used to search for clinical studies. Overall, animal research has shown very promising results in potentiating cognition, both physiologically and behaviourally. However, human studies are limited and results are less consistent, complicating their interpretation. These inconsistencies may be related to differences in methodology and the included population. Taking into account measurements of important inflammatory and antioxidant biomarkers, optimal dosages of curcumin, food interactions, and duration of treatment would increase our understanding on curcumin's promising effects on cognition. In addition, increasing curcumin's bioavailability could benefit future research.

Topics: Aging; Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cognition; Curcumin; Healthy Aging; Humans; Oxidative Stress; Treatment Outcome

The formation of senile plaques and neurofibrillary tangles of the tau protein are the main pathological mechanism of Alzheimer's disease (AD). Current therapies for AD offer discrete benefits to the clinical symptoms and do not prevent the continuing degeneration of neuronal cells. Therefore, novel therapeutic strategies have long been investigated, where curcumin (Curcuma longa) has shown some properties that can prevent the deleterious processes involved in neurodegenerative diseases.. The aim of the present work is to review studies that addressed the effects of curcumin in experimental models (in vivo and in vitro) for AD.. This study is a systematic review conducted between January and June 2017, in which a consultation of scientific articles from indexed periodicals was carried out in Science Direct, United States National Library of Medicine (PubMed), Cochrane Library and Scielo databases, using the following descriptors: "Curcuma longa", "Curcumin" and "Alzheimer's disease".. A total of 32 studies were analyzed, which indicated that curcumin supplementation reverses neurotoxic and behavioral damages in both in vivo and in vitro models of AD.. The administration of curcumin in experimental models seems to be a promising approach in AD, even though it is suggested that additional studies must be conducted using distinct doses and through other routes of administration.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Curcuma; Curcumin; Dietary Supplements; Humans; Neurofibrillary Tangles; Neuroprotective Agents; Plant Extracts; Randomized Controlled Trials as Topic

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disease. Its prominent hallmarks are extracellular deposition of β-amyloids (amyloid plaques), intracellular neurofibrillary tangles (NTFs), neurodegeneration and finally loss of cognitive function. Hence, AD diagnosis in the early stage and monitoring of the disease are of great importance.. In this review article, we have reviewed recent efforts for design, synthesis and evaluation of 99mTc labeled small molecule for AD imaging purposes.. These small molecules include derivatives of Congo red, benzothiazole, benzofuran, benzoxazole, naphthalene, biphenyl, chalcone, flavone, aurone, stilbene, curcumin, dibenzylideneacetone, quinoxaline, etc. The different aspects of 99mTc-labeled small molecules including chemical structure, their affinity toward amyloid plaques, BBB permeation and in vivo/vitro stability will be discussed.. The findings of this review confirm the importance of 99mTc-labeled small molecules for AD imaging. Future studies based on the pharmacophore of these designed compounds are needed for improvement of these molecules for clinical application.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Blood-Brain Barrier; Congo Red; Curcumin; Humans; Organotechnetium Compounds; Small Molecule Libraries; Tomography, Emission-Computed, Single-Photon

Millions of people worldwide are suffering from Alzheimer's disease (AD), and there are only symptomatic treatments available for this disease. Thus, there is a great need to identify drugs capable of arresting or reversing AD. Constituents of the spice turmeric, in particular, curcuminoids, seem to be very promising, as evident from in vitro experiments and tests using animal models of AD. However, most of the clinical trials did not reveal any beneficial effects of curcuminoids in the treatment of AD. These controversies, including conflicting results of clinical trials, are thought to be related to bioavailability of curcuminoids, which is low unless it is enhanced by developing a special formulation. However, there is growing evidence suggesting that other reasons may be of even greater importance, but these avenues are less explored.. Review relevant literature, and analyze potential reasons for the controversial results.. Recent in vitro and preclinical studies; clinical trials (without a limiting period) were searched in PubMed and Google Scholar.. While recent in vitro and preclinical studies confirm the therapeutic potential of curcuminoids in the treatment of AD and cognitive dysfunctions, results of corresponding clinical trials remain rather controversial.. The controversial results obtained in the clinical trials may be in part due to particularities of the curcuminoid formulations other than bioavailability. Namely, it seems likely that the various formulations differ in terms of their minor turmeric constituent(s). We hypothesize that these distinctions may be of key importance for efficacy of the particular formulation in clinical trials. A testable approach addressing this hypothesis is suggested.

Topics: Acid Sensing Ion Channels; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholinesterases; Clinical Trials as Topic; Curcumin; Humans; Insulin; Transient Receptor Potential Channels

Curcumin is a polyphenolic natural compound with diverse and attractive biological activities, which may prevent or ameliorate pathological processes underlying age-related cognitive decline, dementia, or mood disorders. However, clinical trials and animal studies have yielded conflicting conclusions regarding its effectiveness for cognition in different individuals. The aim of this review is to meta-analytically assess the effectiveness of curcumin for cognitive function in different types of people. A preliminary search on PubMed, Embase, Web of Science, ClinicalTrials.gov, Cochrane Library, Chinese National Knowledge Infrastructure, and Wanfang Data and China Biology Medicine disc was performed to identify randomized controlled trials investigating the effect of curcumin on cognition. Six clinical trials with a total of 289 subjects met inclusion criteria for this review. We used a random-effects model to calculate the pooled standardized difference of means (SMD). For older adults who received curcumin, scores on measures of cognitive function (SMD = 0.33, 95% confidence interval [CI] [0.05, 0.62]; p = 0.02), occurrence of adverse events (odds ratio [OR] = 5.59, 95% CI [0.96, 36.80]; p = 0.05), and measures of depression (SMD = -0.29, 95% CI [0.64, 0.05]; p = 0.09) indicated significant memory improvement. In patients with Alzheimer's disease (AD), scores in measures of cognition status (SMD = -0.90, 95% CI [1.48, -0.32]; p = 0.002) indicated that there was a trend for treated subjects to do worse than placebo-treated subjects on the Mini-Mental State Examination. The occurrence of adverse events (OR = 0.87, 95% CI [0.10, 7.51]; p = 0.90) was similar to those who received placebo. Due to insufficient data, it was impossible to provide a narrative account of only the outcomes for schizophrenia. Curcumin appears to be more effective in improving cognitive function in the elderly than in improving symptoms of AD and schizophrenia. Curcumin is also safe and tolerated among these individuals. Because of the small number of studies available, a funnel plot or sensitivity analysis was not possible. Further high-quality trials with larger sample sizes or bioavailability-improved curcumin formulations may be considered for reliable assessment.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; China; Cognition; Cognition Disorders; Curcumin; Depression; Humans

Monocytes and macrophages are important cells of the innate immune system that have diverse functions, including defense against invading pathogens, removal of dead cells by phagocytosis, antigen presentation in the context of MHC class I and class II molecules, and production of various pro-inflammatory cytokines and chemokines such as IL-1β, IL-6, TNF-α and MCP-1. In addition, pro-inflammatory (M1) and anti-inflammatory (M2) macrophages clearly play important roles in the progression of several inflammatory diseases. Therefore, therapies that target macrophage polarization and function by either blocking their trafficking to sites of inflammation, or skewing M1 to M2 phenotype polarization may hold clinical promise in several inflammatory diseases. Dietary-derived polyphenols have potent natural anti-oxidative properties. Within this group of polyphenols, curcumin has been shown to suppress macrophage inflammatory responses. Curcumin significantly reduces co-stimulatory molecules and also inhibits MAPK activation and the translocation of NF-κB p65. Curcumin can also polarize/repolarize macrophages toward the M2 phenotype. Curcumin-treated macrophages have been shown to be highly efficient at antigen capture and endocytosis via the mannose receptor. These novel findings provide new perspectives for the understanding of the immunopharmacological role of curcumin, as well as its therapeutic potential for impacting macrophage polarization and function in the context of inflammation-related disease. However, the precise effects of curcumin on the migration, differentiation, polarization and immunostimulatory functions of macrophages remain unknown. Therefore, in this review, we summarized whether curcumin can influence macrophage polarization, surface molecule expression, cytokine and chemokine production and their underlying pathways in the prevention of inflammatory diseases.

Topics: Alzheimer Disease; Animals; Antigen Presentation; Atherosclerosis; Cell Movement; Cell Polarity; Curcumin; Cytokines; Diet; Humans; Immunologic Factors; Infections; Liver Cirrhosis; Macrophages; Neoplasms; Obesity

Alzheimer's disease (AD) is a major health problem worldwide, with no effective treatment approach. Curcumin is the main ingredient of turmeric traditionally used in Asian medicine. Several experimental studies have indicated the protective effect of curcumin and its novel formulations in AD. Curcumin has antioxidant, anti-inflammatory and neurotrophic activities, proposing a strong potential to prevent neurodegenerative diseases. However, there are no sufficient clinical trials to confirm curcumin use in AD patients. Low bioavailability following oral administration of curcumin limits its usage in human. The present study was designed to gather the effects of curcumin and its modified formulations in human and experimental models of AD.

Topics: Alzheimer Disease; Animals; Brain; Curcumin; Humans; Neuroprotective Agents

Curcumin, a naturally occurring phenolic compound isolated from Curcuma longa, has different pharmacological effects, including antiinflammatory, antimicrobial, antioxidant, and anticancer properties. However, curcumin has been found to have a limited bioavailability because of its hydrophobic nature, low-intestinal absorption, and rapid metabolism. Therefore, there is a need for enhancing the bioavailability and its solubility in water in order to increase the pharmacological effects of this bioactive compound. One strategy is curcumin complexation with transition metals to circumvent the abovementioned problems. Curcumin can undergo chelation with various metal ions to form metallo-complexes of curcumin, which may show greater effects as compared with curcumin alone. Promising results with metal curcumin complexes have been observed with regard to antioxidant, anticancer, and antimicrobial activity, as well as in treatment of Alzheimer's disease. The present review provides a concise summary of the characterization and biological properties of curcumin-metal complexes. © 2019 BioFactors, 45(3):304-317, 2019.

Topics: Alzheimer Disease; Animals; Antioxidants; Curcuma; Curcumin; Humans; Plant Extracts

Curcumin is widely consumed in Asia either as turmeric directly or as one of the culinary ingredients in food recipes. The benefits of curcumin in different organ systems have been reported extensively in several neurological diseases and cancer. Curcumin has got its global recognition because of its strong antioxidant, anti-inflammatory, anti-cancer, and antimicrobial activities. Additionally, it is used in diabetes and arthritis as well as in hepatic, renal, and cardiovascular diseases. Recently, there is growing attention on usage of curcumin to prevent or delay the onset of neurodegenerative diseases. This review summarizes available data from several recent studies on curcumin in various neurological diseases such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Huntington's disease, Prions disease, stroke, Down's syndrome, autism, Amyotrophic lateral sclerosis, anxiety, depression, and aging. Recent advancements toward increasing the therapeutic efficacy of curcuma/curcumin formulation and the novel delivery strategies employed to overcome its minimal bioavailability and toxicity studies have also been discussed. This review also summarizes the ongoing clinical trials on curcumin for different neurodegenerative diseases and patent details of curcuma/curcumin in India.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Anxiety; Autistic Disorder; Biological Availability; Curcuma; Curcumin; Dementia; Depression; Drug Delivery Systems; Glioma; Humans; Huntington Disease; Multiple Sclerosis; Muscular Atrophy, Spinal; Neuroprotective Agents; Parkinson Disease; Patents as Topic; Prion Diseases; Stroke

Alzheimer's disease (AD) is the most common neurodegenerative disease causing dementia in the elderly population. Due to the fact that there is still no cure for Alzheimer's dementia and available treatment strategies bring only symptomatic benefits, there is a pressing demand for other effective strategies such as diet. Since the inflammation hypothesis gained considerable significance in the AD pathogenesis, elucidating the modulatory role of dietary factors on inflammation may help to prevent, delay the onset and slow the progression of AD. Current evidence clearly shows that synergistic action of combined supplementation and complex dietary patterns provides stronger benefits than any single component considered separately. Recent studies reveal the growing importance of novel factors such as dietary advanced glycation end products (d-AGE), gut microbiota, butyrate and vitamin D. This paper summarizes the available evidence of pro- and anti-inflammatory activity of some dietary components including fatty acids, vitamins, flavonoids, polyphenols, probiotics and d-AGE, and their potential for AD prevention and treatment.

Topics: Alzheimer Disease; Butyrates; Caffeine; Cholecalciferol; Curcumin; Diet; Dietary Supplements; Encephalitis; Fatty Acids; Fatty Acids, Omega-3; Gastrointestinal Microbiome; Glycation End Products, Advanced; Humans; Meat; Resveratrol; Vitamin B Complex

Neurodegenerative disease is an incurable disease which involves the degeneration or death of the nerve cells. Alzheimer's Disease (AD) is a neurodegenerative disease discovered in 1906 by Alois Alzheimer, a German clinical psychiatrist and neuroanatomist. The main pathological hallmarks of this disease are the formation of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangle (NFT). The accumulation of the amyloid protein aggregates in the brain of AD patients leads to oxidative stress and inflammation. Other postulated reasons for the development of this disease are cholinergic depletion and excessive glutamatergic neurotransmission. The current drugs approved and marketed for the treatment of AD are cholinesterase inhibitors (ChEIs) and N-methyl-Daspartate (NMDA) receptor antagonists. The function of ChEIs is to avoid cholinergic depletion; whereas the function of NMDA receptor antagonist is to block excessive glutamatergic neurotransmission. Unfortunately, the current drugs prescribed for AD show only modest improvement in terms of symptomatic relief and delay the progression of the disease. This review will discuss about several polyphenolic compounds as potential natural treatment options for AD. Three compounds are highlighted in this review - Curcumin (Cur), Resveratrol (Rsv) and Epigallocatechin-3- gallate (EGCG). These compounds have huge potential for AD treatment, especially due to their low frequency of adverse events. However, the current conventional pharmaceutical drugs remain as the mainstay of treatment for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Catechin; Curcumin; Disease Progression; Humans; Neuroprotective Agents; Oxidative Stress; Polyphenols; Resveratrol

Since its discovery some hundred years ago, Alzheimer's disease (AD), a neurodegenerative disease and an eminent cause of most dementia, continues to pose problems for affected families and society, especially in developed countries. With the approved medications by the Food and Drugs Administration in the United States, effectual treatment of AD apropos to the complete eradication of the disease continues to be elusive due to complexities relating to the pathophysiology of the disease. Nutrition has and continues to play a salient role in the survival of living organisms with no exception for human beings. Herein, we report the connection between nutrition and AD with particular attention to vitamins, curcumin, and the Mediterranean diet.

Topics: Alzheimer Disease; Curcumin; Diet, Mediterranean; Dietary Supplements; Humans; Nutritional Status; Risk Factors; Vitamins

The purpose of our article is to assess the current understanding of Indian spice, curcumin, against amyloid-β (Aβ)-induced toxicity in Alzheimer's disease (AD) pathogenesis. Natural products, such as ginger, curcumin, and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes, and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on Aβ and curcumin has revealed that curcumin prevents Aβ aggregation and crosses the blood-brain barrier, reach brain cells, and protect neurons from various toxic insults of aging and Aβ in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin's bioavailability and urgent need for new formulations to increase its brain levels to treat patients with AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Curcumin; Disease Models, Animal; Humans; Mice; Neuroprotective Agents; Randomized Controlled Trials as Topic; Spices

The β-amyloid (Aβ) plaques presented within the brain parenchyma have been widely proved to be one of the hallmarks of Alzheimer's disease (AD). According to the amyloid cascade hypothesis, the accumulation of Aβ plaques in the brain is intrinsic and fundamental for disease onset, and much research about the early diagnosis of AD is based on this. A recent development in Aβ detection has focused on the mapping of the molecule events in the brain using an exquisite, noninvasive, and inexpensive optical imaging technique, which has stimulated the rapid development of Aβ-specific fluorescent probes. Among them, nearinfrared (NIR) fluorophores have gained adequate attention due to the weak light attenuation in tissues and avoidance from auto-fluorescence of biological matter. In this review, we showcase the current developments of fluorescent probes that are subject to in vitro or in vivo detection of Aβ plaques in the brain, and give an emphasis on the probes used for in vivo twophoton microscopy and NIR imaging by highlighting their biological and photochemical properties.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzothiazoles; Brain; Congo Red; Curcumin; Fluorescent Dyes; Humans; Microscopy, Fluorescence, Multiphoton; Positron Emission Tomography Computed Tomography; Thiazoles

In recent years, ongoing interest in ischemic brain injury research has provided data showing that ischemic episodes are involved in the development of Alzheimer's disease-like neuropathology. Brain ischemia is the second naturally occurring neuropathology, such as Alzheimer's disease, which causes the death of neurons in the CA1 region of the hippocampus. In addition, brain ischemia was considered the most effective predictor of the development of full-blown dementia of Alzheimer's disease phenotype with a debilitating effect on the patient. Recent knowledge on the activation of Alzheimer's disease-related genes and proteins-e.g., amyloid protein precursor and tau protein-as well as brain ischemia and Alzheimer's disease neuropathology indicate that similar processes contribute to neuronal death and disintegration of brain tissue in both disorders. Although brain ischemia is one of the main causes of death in the world, there is no effective therapy to improve the structural and functional outcomes of this disorder. In this review, we consider the promising role of the protective action of curcumin after ischemic brain injury. Studies of the pharmacological properties of curcumin after brain ischemia have shown that curcumin has several therapeutic properties that include anti-excitotoxic, anti-oxidant, anti-apoptotic, anti-hyperhomocysteinemia and anti-inflammatory effects, mitochondrial protection, as well as increasing neuronal lifespan and promoting neurogenesis. In addition, curcumin also exerts anti-amyloidogenic effects and affects the brain's tau protein. These results suggest that curcumin may be able to serve as a potential preventive and therapeutic agent in neurodegenerative brain disorders.

Topics: Alzheimer Disease; Animals; Brain Ischemia; Curcumin; Humans; Neuroprotective Agents; Nootropic Agents; Phenotype

Progress in chronobiology thus far has been built on botanical field investigation records, experiments on the development of biological clocks, open questions, established rules, and molecular mechanisms. In this review, three clock-related diseases, namely cancer, Alzheimer's disease (AD), and depression, are discussed. Evidence-based mechanisms of action of active compounds, namely epigallocatechin-3-gallate (EGCG), curcumin, and melatonin, from three medicinal plants, Camellia sinensis K., Curcuma longa L., and Hypericum perforatum L., respectively, as potential therapies against cancer, AD, and depression, respectively, have been explained. Feedback loops of basic inputs and application outputs of various studies will lead to the development of chronobiology for applications in time-keeping, disease prevention, and control, and future agricultural practices.

Topics: Agriculture; Alzheimer Disease; Biological Clocks; Camellia sinensis; Curcuma; Depression; Humans; Hypericum; Neoplasms; Plants, Medicinal

Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly. As the prevalence of AD rises in the 21st century, there is an urgent need for the development of effective pharmacotherapies. Currently, drug treatments target the symptoms of the disease and do not modify or halt the disease progress. Thus, natural compounds have been investigated for their ability to treat AD. This review examines the efficacy of curcumin, a polyphenol derived from turmeric herb, to treat AD. We summarize the in vivo and in vitro research describing the mechanisms of action in which curcumin modifies AD pathology: curcumin inhibits the formation and promotes the disaggregation of amyloid-β plaques, attenuates the hyperphosphorylation of tau and enhances its clearance, binds copper, lowers cholesterol, modifies microglial activity, inhibits acetylcholinesterase, mediates the insulin signaling pathway, and is an antioxidant. In conclusion, curcumin has the potential to be more efficacious than current treatments. However, its usefulness as a therapeutic agent may be hindered by its low bioavailability. If the challenge of low bioavailability is overcome, curcumin-based medications for AD may be in the horizon.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents; Curcumin; Disease Progression; Humans

The purpose of this article is to introduce the role of turmeric in medicine and summarize the current state of research on its applications. Turmeric (Curcuma longa) has had a wide range of uses in middle eastern and orietnal traditional medicine. Currently, however, its use has been truncated to a common cooking spice, despite numerous studies pointing to its healing properties and possible use in the treatment of many diseases. The main focus is on curcumin, a polyphenol which serves as the biologically active component of turmeric. Curcumin's anti-inflammatory effects have been well documented in medical studies, with wide ranging applications from the treatment of rheumatologic diseases such as arthritis to dermatology, with significant effects in the treatment of psoriasis, acne and in relieving of itching. In addition to the effect of pro-inflammatory cytokines, curcumin can also accelerate healing of skin wounds. Apart from controlling the body's inflammatory response, curcumin has a bacteriostatic effect, which has been shown to be an important factor in the treatment of diseases with complex etiology. Additionally, studies show that curcumin's effects on oncogenesis, the process of metastasis, angiogenesis, apoptosis or response to cytostatic drugs have yielded promising results. It has been confirmed that its antioxidant effect correlates with a decrease in LDL levels in blood and to a reduced risk of atherosclerosis. Curcumin consumption has also been shown to have a vasodilating effect through its indirect impact on prostacyclins and directly on vascular endothelium. Many of the mention medicinal properties of turmeric are still the subject of research and debate; as such, only some of them have entered the phase of clinical trials.

Topics: Alzheimer Disease; Anti-Inflammatory Agents; Antineoplastic Agents; Curcuma; Curcumin; Humans; Plants, Medicinal; Protective Agents; Skin Diseases; Spices; Wound Healing

Population aging is an irreversible global trend with economic and socio-political consequences. One of the most invalidating outcomes of aging in the elderly is cognitive decline, leading to dementia and often related to neurodegenerative disorders. Among these latter, Alzheimer's disease (AD) is the major cause of dementia, affecting more than 30 million of individuals worldwide. To date, the treatment of AD remains a challenge because of an incomplete understanding of the events that lead to the selective neurodegeneration typical of Alzheimer's brains. There is an enormous global demand for new effective therapies and researchers are investigating new fields. One promising strategy is the use of nutraceuticals as integrative, complementary and preventive therapy. Curcumin is one example of natural product with anti-AD properties, with promising potential for prevention, treatment and diagnostic. The limitations in the use of curcumin as therapeutic are represented by its pharmacokinetics profile and the low bioavailability after oral administration. However, curcumin has been the focus of intense research for new drug development. Here we analyzed some new approaches that have been applied in the attempt to improve its use, particularly new formulations, changes in the way of administration, nanotechnology-based delivery systems and the hybridization strategy.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Drug Compounding; Drug Delivery Systems; Humans; Neuroprotective Agents

Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting 25 million people worldwide, and cholinergic hypothesis is considered as an important hypotheses in the processes of improving cognitive function and recognition skills in recent years. For the long-term treatment of AD, traditional Chinese medicine are particularly suitable for drug discovery. In this review, we sum up six traditional Chinese medicinal herbs concerned with development of AChEIs, including Herba Epimedii, Coptis Chinensis Franch, Rhizoma Curcumae Longae, Green tea, Ganoderma, Panax Ginseng. The listed compounds based on these herbs are belonging to six classes Flavonoids, Alkaloids, Ketones, Polyphenols, Terpenoid and Saponins, respectively. These compounds could be very promising agents in the search for potent anti-Alzheimer's drugs.

Topics: Acetylcholinesterase; Alzheimer Disease; Berberine; Cholinesterase Inhibitors; Curcumin; Drugs, Chinese Herbal; Flavonoids; Ginsenosides; Humans; Medicine, Chinese Traditional

Ferulic acid, a natural phytochemical has gained importance as a potential therapeutic agent by virtue of its easy commercial availability, low cost and minimal side-effects. It is a derivative of curcumin and possesses the necessary pharmacokinetic properties to be retained in the general circulation for several hours. The therapeutic effects of ferulic acid are mediated through its antioxidant and anti-inflammatory properties. It exhibits different biological activities such as anti-inflammatory, anti-apoptotic, anti-carcinogenic, anti-diabetic, hepatoprotective, cardioprotective, neuroprotective actions, etc. The current review addresses its therapeutic effects under different pathophysiological conditions (eg. cancer, cardiomyopathy, skin disorders, brain disorders, viral infections, diabetes etc.).

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Apoptosis; Cardiomyopathies; Cell Differentiation; Coumaric Acids; Curcumin; Diabetes Complications; Humans; Inflammation; Parkinson Disease; Schwann Cells; Skin Diseases

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by deposition of amyloid plaques and neurofibrillary tangles, as well as microglial and astroglial activation, and, finally, leading to neuronal dysfunction and death. Current treatments for AD primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for the treatment of AD patients. This review will provide an overview of the antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of a variety of nutraceuticals including curcumin, apigenin, docosahexaenoic acid, epigallocatechin gallate, α-lipoic acid and resveratrol and their potential for AD prevention and treatment. We suggest that therapeutic use of these compounds might lead to a safe strategy to delay the onset of AD or slow down its progression. The continuing investigation of the potential of these substances is necessary as they are promising compounds to yield a possible remedy for this pervasive disease.

Topics: Alzheimer Disease; Animals; Antioxidants; Biological Products; Chronic Disease; Curcumin; Fish Oils; Humans; Inflammation; Neurodegenerative Diseases; Neurofibrillary Tangles; Neuroprotective Agents; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes

Curcumin derived from turmeric is well documented for its anti-carcinogenic, antioxidant and anti-inflammatory properties. Recent studies show that curcumin also possesses neuroprotective and cognitive-enhancing properties that may help delay or prevent neurodegenerative diseases, including Alzheimer's disease (AD). Currently, clinical diagnosis of AD is onerous, and it is primarily based on the exclusion of other causes of dementia. In addition, phase III clinical trials of potential treatments have mostly failed, leaving disease-modifying interventions elusive. AD can be characterised neuropathologically by the deposition of extracellular β amyloid (Aβ) plaques and intracellular accumulation of tau-containing neurofibrillary tangles. Disruptions in Aβ metabolism/clearance contribute to AD pathogenesis. In vitro studies have shown that Aβ metabolism is altered by curcumin, and animal studies report that curcumin may influence brain function and the development of dementia, because of its antioxidant and anti-inflammatory properties, as well as its ability to influence Aβ metabolism. However, clinical studies of curcumin have revealed limited effects to date, most likely because of curcumin's relatively low solubility and bioavailability, and because of selection of cohorts with diagnosed AD, in whom there is already major neuropathology. However, the fresh approach of targeting early AD pathology (by treating healthy, pre-clinical and mild cognitive impairment-stage cohorts) combined with new curcumin formulations that increase bioavailability is renewing optimism concerning curcumin-based therapy. The aim of this paper is to review the current evidence supporting an association between curcumin and modulation of AD pathology, including in vitro and in vivo studies. We also review the use of curcumin in emerging retinal imaging technology, as a fluorochrome for AD diagnostics.

Topics: Alzheimer Disease; Animals; Cognition; Curcumin; Disease Models, Animal; Fluorescent Dyes; Humans; Neurofibrillary Tangles; Neuroprotective Agents; Nootropic Agents; Radioligand Assay; Randomized Controlled Trials as Topic

With accumulating evidence suggesting that amyloid-β (Aβ) deposition is a good diagnostic biomarker for Alzheimer's disease (AD), the discovery of active Aβ probes has become an active area of research. Among the existing imaging methods, optical imaging targeting Aβ aggregates (fibrils or oligomers), especially using near-infrared (NIR) fluorescent probes, is increasingly recognized as a promising approach for the early diagnosis of AD due to its real time detection, low cost, lack of radioactive exposure and high-resolution. In the past decade, a variety of fluorescent probes have been developed and tested for efficiency in vitro, and several probes have shown efficacy in AD transgenic mice. This review classifies these representative probes based on their chemical structures and functional modes (dominant solvent-dependent mode and a novel solvent-independent mode). Moreover, the pharmaceutical characteristics of these representative probes are summarized and discussed. This review provides important perspectives for the future development of novel NIR Aβ diagnostic probes.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzothiazoles; Boron Compounds; Curcumin; Fluorescent Dyes; Humans; Optical Imaging; Stilbenes; Thiazoles; Thiophenes

Alzheimer's disease (AD), the most common neurodegenerative disorder associated with dementia, not only severely decreases the quality of life for its victims, but also brings a heavy economic burden to the family and society. Unfortunately, few chemical drugs designed for clinical applications have reached the expected preventive or therapeutic effect so far, and combined with their significant side-effects, there is therefore an urgent need for new strategies to be developed for AD treatment. Traditional Chinese Medicine has accumulated many experiences in the treatment of dementia during thousands of years of practice; modern pharmacological studies have confirmed the therapeutic effects of many active components derived from Chinese herbal medicines (CHM). Ginsenoside Rg1, extracted from Radix Ginseng, exerts a [Formula: see text]-secretase inhibitor effect so as to decrease A[Formula: see text] aggregation. It can also inhibit the apoptosis of neuron cells. Tanshinone IIA, extracted from Radix Salviae miltiorrhizae, and baicalin, extracted from Radix Scutellariae[Formula: see text] can inhibit the oxidative stress injury in neuronal cells. Icariin, extracted from Epimedium brevicornum, can decrease A[Formula: see text] levels and the hyperphosphorylation of tau protein, and can also inhibit oxidative stress and apoptosis. Huperzine A, extracted from Huperzia serrata, exerts a cholinesterase inhibitor effect. Evodiamine, extracted from Fructus Evodiae, and curcumin, extracted from Rhizoma Curcumae Longae, exert anti-inflammatory actions. Curcumin can act on A[Formula: see text] and tau too. Due to the advantages of multi-target effects and fewer side effects, Chinese medicine is more appropriate for long-term use. In this present review, the pharmacological effects of commonly used active components derived from Chinese herbal medicines in the treatment of AD are discussed.

Topics: Abietanes; Alkaloids; Alzheimer Disease; Curcuma; Curcumin; Drugs, Chinese Herbal; Epimedium; Evodia; Flavonoids; Ginsenosides; Humans; Huperzia; Panax; Phytotherapy; Plant Extracts; Quinazolines; Salvia miltiorrhiza; Scutellaria baicalensis; Sesquiterpenes

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which usually occurs in the elderly. The accumulation of β-amyloid and the formation of neurofibrillary tangles are considered as the main pathogenies of AD. Research suggests that β-secretase 1 (BACE1) plays an important role in the formation of β-amyloid. Discovery of new BACE1 inhibitors has become a significant method to slow down the progression of AD or even cure this kind of disease. This review summarizes the different types and the structural modification of these new BACE1 inhibitors.

Topics: Alkaloids; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Aspartic Acid; Aspartic Acid Endopeptidases; Curcumin; Enzyme Inhibitors; Gene Expression; Humans; Hydrophobic and Hydrophilic Interactions; Neuroprotective Agents; Peptidomimetics; Piperazines; Structure-Activity Relationship; Terpenes

Oxidative stress and inflammatory response are important elements of Alzheimer's disease (AD) pathogenesis, but the role of redox signaling cascade and its cross-talk with inflammatory mediators have not been elucidated in details in this disorder. The review summarizes the facts about redox-signaling cascade in the cells operating through an array of kinases, phosphatases and transcription factors and their downstream components. The biology of NF-κB and its activation by reactive oxygen species (ROS) and proinflammatory cytokines in the pathogenesis of AD have been specially highlighted citing evidence both from post-mortem studies in AD brain and experimental research in animal or cell-based models of AD. The possibility of identifying new disease-modifying drugs for AD targeting NF-κBsignaling cascade has been discussed in the end.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Brain; Curcumin; Cytokines; Diterpenes, Kaurane; Gene Expression Regulation; Humans; Mice; Neuroprotective Agents; NF-kappa B; Oxidative Stress; Reactive Oxygen Species; Signal Transduction

The adult brain of humans and other mammals continuously generates new neurons throughout life. However, this neurogenic capacity is limited to two brain areas, the dentate gyrus (DG of the hippocampus and the subventricular zone (SVZ of the lateral ventricle. Although the DG generates new neurons, its neurogenic capacity declines with age and neurodegenerative diseases such as Alzheimer's disease (AD and Huntington's disease (HD. This review focuses on the role of newly-born neurons in cognitive processes, and discusses some of the strategies proposed in humans and animals to enhance neurogenesis and counteract age-related cognitive deficits, such as physical exercise and intake of natural products like omega-3 fatty acids, curcumin and flavanols.

Topics: Aging; Alzheimer Disease; Animals; Cognition Disorders; Curcumin; Exercise; Fatty Acids, Omega-3; Flavonols; Hippocampus; Humans; Huntington Disease; Life Style; Neurodegenerative Diseases; Neurogenesis

For thousands of years, humankind has used plants for therapeutics. Nowadays, there is a renewed public interest in naturally occurring treatments with minimal toxicity and diets related to health. Alterations in hippocampal neurogenesis have been recognized as an integral part of brain ischemia. Neuronal stem/progenitor cells in the hippocampus are positively and negatively regulated by intrinsic and extrinsic agents. One positive regulator of neurogenesis in the hippocampus is curcumin in the diet. This review provides an assessment of the current state of the field in hippocampal neurogenesis and neuroprotection studies in brain ischemia and focuses on the role of curcumin in the diet. Data suggest that dietary intake of curcumin enhances neurogenesis. Recent studies performed in ischemic models have suggested that curcumin also has neuroprotective features. One potential mechanism to explain several of the general health benefits associated with curcumin is that it may prevent ageing-associated changes in cellular proteins that lead to protein insolubility and aggregation after ischemia such as β-amyloid peptide and tau protein. Here, we also review the evidence from ischemic models that curcumin improves cognition and health span by overexpression of life supporting genes and preventing or delaying the onset of neurodegenerative changes. Available data provide evidence that curcumin induces neurogenesis and neuroprotection and may provide a novel therapeutic agent for both regenerative medicine and for the treatment of neurodegenerative diseases such as postischemic brain neurodegeneration with Alzheimer phenotype.

Topics: Alzheimer Disease; Animals; Brain; Brain Ischemia; Curcumin; Humans; Nerve Degeneration; Neurogenesis; Neuroprotective Agents; Phenotype

There is a crucial need to develop new effective drugs for Alzheimer's disease (AD) as the currently available AD treatments provide only momentary and incomplete symptomatic relief. Amongst natural products, curcumin, a major constituent of turmeric, has been intensively investigated for its neuroprotective effect against β-amyloid (Aβ)-induced toxicity in cultured neuronal cells. The ability of curcumin to attach to Aβ peptide and prevent its accumulation is attributed to its three structural characteristics such as the presence of two aromatic end groups and their co-planarity, the length and rigidity of the linker region and the substitution conformation of these aromatics. However, curcumin failed to reach adequate brain levels after oral absorption in AD clinical trials due to its low water solubility and poor oral bioavailability. A number of new curcumin analogs that mimic the active site of the compound along with analogs that mimic the curcumin anti-amyloid effect combined with anticholinesterase effect have been developed to enhance the bioavailability, pharmacokinetics, water solubility, stability at physiological conditions and delivery of curcumin. In this article, we have summarized all reported synthetic analogs of curcumin showing effects on β-amyloid and discussed their potential as therapeutic and diagnostic agents for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Curcumin; Humans; Neuroprotective Agents; Protein Aggregates; Protein Aggregation, Pathological

Curcumin is the major yellow pigment extracted from turmeric, a commonly used spice in Asian cuisine and extensively employed in ayurvedic herbal remedies. A number of studies have shown that curcumin can be a prevention and a chemotherapeutic agent for colon, skin, oral and intestinal cancers. Curcumin is also well known for its antiinflammatory and antioxidant properties, showing high reactivity towards peroxyl radicals, and thus acting as a free radical scavenger. Recently, experimental studies have demonstrated that curcumin might be used in the prevention and the cure of Alzheimer's disease. Indeed, curcumin injected peripherally in vivo into aged Tg mice crossed the blood-brain barrier and bound to amyloid plaques, reducing amyloid levels and plaque formation decisively. The present review will resume the most recent developments in the medicinal chemistry of curcumin and curcumin-like molecules.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antioxidants; Chemistry, Pharmaceutical; Curcumin; Humans; Molecular Structure; Neoplasms

Alzheimer's disease (AD) is the most common form of dementia. There is limited choice in modern therapeutics, and drugs available have limited success with multiple side effects in addition to high cost. Hence, newer and alternate treatment options are being explored for effective and safer therapeutic targets to address AD. Turmeric possesses multiple medicinal uses including treatment for AD. Curcuminoids, a mixture of curcumin, demethoxycurcumin, and bisdemethoxycurcumin, are vital constituents of turmeric. It is generally believed that curcumin is the most important constituent of the curcuminoid mixture that contributes to the pharmacological profile of parent curcuminoid mixture or turmeric. A careful literature study reveals that the other two constituents of the curcuminoid mixture also contribute significantly to the effectiveness of curcuminoids in AD. Therefore, it is emphasized in this review that each component of the curcuminoid mixture plays a distinct role in making curcuminoid mixture useful in AD, and hence, the curcuminoid mixture represents turmeric in its medicinal value better than curcumin alone. The progress in understanding the disease etiology demands a multiple-site-targeted therapy, and the curcuminoid mixture of all components, each with different merits, makes this mixture more promising in combating the challenging disease.

Topics: Alzheimer Disease; Animals; Curcuma; Curcumin; Diarylheptanoids; Humans; Molecular Structure; Phytotherapy

Dementia is a leading health problem worldwide, with Alzheimer's disease (AD) representing up to 60% of all dementia cases. A growing interest has recently risen on the potential use of natural molecules in this condition. Curcumin is a polyphenolic compound traditionally used in Indian medicine. Several in vitro and in vivo studies have found a protective effect of curcumin in AD. In the present systematic review we aimed to evaluate the state-of-the-art of clinical trials of curcumin in AD. We retrieved three published studies, while there are several ongoing clinical trials. To date there is insufficient evidence to suggest the use of curcumin in dementia patients. Of note, short-term use of curcumin appears to be safe. Several reasons could be responsible for the discrepancy between in vitro and in vivo findings and human trials, such as low bioavailability and poor study design.

Topics: Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Curcumin; Humans

Neurodegenerative disorders and diseases (NDDs) that are either chronically acquired or triggered by a singular detrimental event are a rapidly growing cause of disability and/or death. In recent times, there have been major advancements in our understanding of various neurodegenerative disease states that have revealed common pathologic features or mechanisms. The many mechanistic parallels discovered between various neurodegenerative diseases suggest that a single therapeutic approach may be used to treat multiple disease conditions. Of late, natural compounds and supplemental substances have become an increasingly attractive option to treat NDDs because there is growing evidence that these nutritional constituents have potential adjunctive therapeutic effects (be it protective or restorative) on various neurodegenerative diseases. Here we review relevant experimental and clinical data on supplemental substances (i.e., curcuminoids, rosmarinic acid, resveratrol, acetyl-L-carnitine, and ω-3 (n-3) polyunsaturated fatty acids) that have demonstrated encouraging therapeutic effects on chronic diseases, such as Alzheimer's disease and neurodegeneration resulting from acute adverse events, such as traumatic brain injury.

Topics: Acetylcarnitine; Alzheimer Disease; Brain; Brain Injuries; Cinnamates; Cognition Disorders; Curcumin; Depsides; Diet; Dietary Supplements; Fatty Acids, Omega-3; Humans; Neurodegenerative Diseases; Oxidative Stress; Polyphenols; Resveratrol; Rosmarinic Acid; Stilbenes

Alzheimer's disease is a chronic neurodegenerative disorder characterized by progressive dementia and deterioration of cognitive function. Although several drugs currently used for the treatment of Alzheimer's disease delay its onset and slow its progression, still there is no drug with profound disease-modifying effects. Studies aiming the treatment of this neurodegenerative disorder explore various disease mechanisms. Since antiquity, medicinal herbs have been used in traditional medicine. Recent studies suggest that the neurobiological effects of phytochemicals from medicinal herbs may contribute to clinical benefits in in vitro and in vivo models of Alzheimer's disease. This review focuses on five phytochemicals, berberine, curcumin, ginsenoside Rg1, puerarin, and silibinin, which have been mostly investigated to treat the development and progression of this neurodegenerative disorder.

Topics: Alzheimer Disease; Animals; Berberine; Coptis; Curcuma; Curcumin; Ginsenosides; Humans; Isoflavones; Panax notoginseng; Phytochemicals; Plants, Medicinal; Pueraria; Silybin; Silybum marianum; Silymarin

Polyphenols are the most abundant components of our daily food, occupying the major portion of naturally occurring phytochemicals in plants. Currently, polyphenols have received a special attention from the scientific community against health risk because of their antioxidant capacity and the ability to scavenge the free radicals formed during the pathological process like cancer, cardiovascular diseases and neurodegenerative disorders. Alzheimer's disease, one of the common forms of dementia is an intricate, multifactorial mental illness which is characterized by age-dependent memory loss ultimately leading to a steady decline of cognitive function. Extracellular amyloid beta deposition and intracellular tau hyperphosphorylation are the two main alterations occurring in the cells reported to cause neuronal dysfunction during AD. Dietary intake of polyphenols is known to attenuate the progression of the disease by showing strong potential to tackle the alterations and reduce the risk of AD by reversing the cognitive deficits. A large number of polyphenolic compounds showing promising results against AD pathologies have been identified and described in the past decade. Many efforts have been made to unravel the molecular mechanisms and the specific interactions of polyphenols with their targets in the pathway. This review focuses on the therapeutic potential and promising role of dietary polyphenols as nutraceuticals to combat AD.

Topics: Alzheimer Disease; Animals; Coumaric Acids; Curcumin; Diet; Flavonoids; Humans; Research; Resveratrol; Stilbenes

The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of misfolding, while others are selectively tagged for removal by heat shock proteins and degraded by either the proteasome or phagosomes. These systems are compromised in different neurodegenerative diseases. Therefore, developing novel targets and classes of therapeutic drugs, which can reduce aggregates and maintain proteostasis in the brains of neurodegenerative models, is vital. Natural products that can modulate heat shock proteins/proteosomal pathway are considered promising for treating neurodegenerative diseases. Here we discuss the current knowledge on the role of HSPs in protein misfolding diseases and knowledge gained from animal models of Alzheimer's disease, tauopathies, and Huntington's diseases. Further, we discuss the emerging treatment regimens for these diseases using natural products, like curcumin, which can augment expression or function of heat shock proteins in the cell.

Topics: Alzheimer Disease; Curcumin; Heat-Shock Proteins; Humans; Huntington Disease; Molecular Chaperones; Neurodegenerative Diseases; Protein Aggregation, Pathological; Protein Folding; Proteostasis Deficiencies; Ubiquitin

As demographics in developed nations shift towards an aging population, neurodegenerative pathologies, especially dementias such as Alzheimer's disease, pose one of the largest challenges to the modern health care system. Since there is yet no cure for dementia, there is great pressure to discover potential therapeutics for these diseases. One popular candidate is curcumin or diferuloylmethane, a polyphenolic compound that is the main curcuminoid found in Curcuma longa (family Zingiberaceae). In recent years, curcumin has been reported to possess anti-amyloidogenic, antiinflammatory, anti-oxidative, and metal chelating properties that may result in potential neuroprotective effects. Particularly, the hydrophobicity of the curcumin molecule hints at the possibility of blood-brain barrier penetration and accumulation in the brain. However, curcumin exhibits extremely low bioavailability, mainly due to its poor aqueous solubility, poor stability in solution, and rapid intestinal first-pass and hepatic metabolism. Despite the many efforts that are currently being made to improve the bioavailability of curcumin, brain concentration of curcumin remains low. Furthermore, although many have reported that curcumin possesses a relatively low toxicity profile, curcumin applied at high doses, which is not uncommon practice in many in vivo and clinical studies, may present certain dangers that in our opinion have not been addressed sufficiently. Herein, the neuroprotective potential of curcumin, with emphasis on Alzheimer's disease, as well as its limitations will be discussed in detail.

Topics: Alzheimer Disease; Biological Availability; Curcumin; Drug Stability; Humans; Neuroprotective Agents; Research; Solubility

Curcumin has been estimated as a potential agent for many diseases and attracted great attention owing to its various pharmacological activities, including anti-cancer, and anti-inflammatory. Now curcumin is being applied to a number of patients with breast cancer, rheumatoid arthritis, Alzheimer's disease, colorectal cancer, psoriatic, etc. Several clinical trials have stated that curcumin is safe enough and effective. The objective of this article was to summarize the clinical studies of curcumin, and give a reference for future studies.

Topics: Alzheimer Disease; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Cardiovascular Agents; Clinical Trials as Topic; Curcumin; Gallbladder; Humans; Treatment Outcome

Definite Alzheimer's disease (AD) diagnosis at early stages is vital for targeting intervention, yet currently unavailable. Noninvasive detection of the pathological hallmark, amyloid-β protein (Aβ) plaques, is limited in the brain. However, the existence of Aβ plaques in the retina, possibly at presymptomatic stages, may improve early detection of AD.. To summarize clinical and preclinical evidence showing that the retina, an accessible part of the central nervous system, displays abnormalities in AD, especially Aβ plaque pathology. The ability to monitor in vivo retinal plaque dynamics in response to immunotherapy is also assessed.. Literature analysis of retinal AD pathology and imaging is provided. In our studies, systemic curcumin is administered to enable monitoring of retinal Aβ plaques in live APP(SWE)/PS1(Δ)(E9) transgenic mice by optical imaging.. Visual and retinal abnormalities, including early manifestation of retinal Aβ plaque pathology, have been documented in AD patients and animal models. In mouse models, retinal Aβ plaques accumulate with age and decrease in response to immunotherapy, consistent with brain pathology. Here, we demonstrate that retinal plaques can be individually monitored in real time following glatiramer acetate immunization.. Translation of noninvasive retinal-plaque imaging to humans could eventually facilitate early and accurate AD diagnosis and therapy assessment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Curcumin; Disease Models, Animal; Early Diagnosis; Humans; Mice; Mice, Transgenic; Neuroimaging; Presenilin-1; Retina; Vision Disorders

Alzheimer's disease (AD) is a severe chronic neurodegenerative disorder of the brain characterised by progressive impairment in memory and cognition. In the past years an intense research has aimed at dissecting the molecular events of AD. However, there is not an exhaustive knowledge about AD pathogenesis and a limited number of therapeutic options are available to treat this neurodegenerative disease. Consequently, considering the heterogeneity of AD, therapeutic agents acting on multiple levels of the pathology are needed. Recent findings suggest that phytochemicals compounds with neuroprotective features may be an important resources in the discovery of drug candidates against AD. In this paper we will describe some polyphenols and we will discuss their potential role as neuroprotective agents. Specifically, curcumin, catechins, and resveratrol beyond their antioxidant activity are also involved in antiamyloidogenic and anti-inflammatory mechanisms. We will focus on specific molecular targets of these selected phytochemical compounds highlighting the correlations between their neuroprotective functions and their potential therapeutic value in AD.

Topics: Alzheimer Disease; Catechin; Curcumin; Humans; Neuroprotective Agents; NF-E2-Related Factor 2; Polyphenols; Resveratrol; Stilbenes

In this review, we elucidate the mechanisms of Aβ oligomer toxicity which may contribute to Alzheimer's disease (AD). In particular, we discuss on the interaction of Aβ oligomers with the membrane through the process of adsorption and insertion. Such interaction gives rises to phase transitions in the sub-structures of the Aβ peptide from α-helical to β-sheet structure. By means of a coarse-grained model, we exhibit the tendency of β-sheet structures to aggregate, thus providing further insights to the process of membrane induced aggregation. We show that the aggregated oligomer causes membrane invagination, which is a precursor to the formation of pore structures and ion channels. Other pathological progressions to AD due to Aβ oligomers are also covered, such as their interaction with the membrane receptors, and their direct versus indirect effects on oxidative stress and intraneuronal accumulation. We further illustrate that the molecule curcumin is a potential Aβ toxicity inhibitor as a β-sheet breaker by having a high propensity to interact with certain Aβ residues without binding to them. The comprehensive understanding gained from these current researches on the various toxicity mechanisms show promises in the provision of better therapeutics and treatment strategies in the near future.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Membrane; Curcumin; Humans; Protein Aggregation, Pathological; Protein Structure, Secondary

Polyphenolic compounds derived mainly from plant products have demonstrated neuroprotective properties in a number of experimental settings. Such protective effects have often been ascribed to antioxidant capacity, but specific augmentation of other cellular defences and direct interactions with neurotoxic proteins have also been demonstrated. With an emphasis on neurodegenerative conditions, such as Alzheimer's disease, we highlight recent findings on the neuroprotection ascribed to bioactive polyphenols capable of directly interfering with the Alzheimer's disease hallmark toxic β-amyloid protein (Aβ), thereby inhibiting fibril and aggregate formation. This includes compounds such as the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) and the phytoalexin resveratrol. Targeted studies on the biomolecular interactions between dietary polyphenolics and Aβ have not only improved our understanding of the pathogenic role of β-amyloid, but also offer fundamentally novel treatment options for Alzheimer's disease and potentially other amyloidoses.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Catechin; Cell Line; Curcumin; Diet; Humans; Models, Molecular; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Plants; Polyphenols; Resveratrol; Stilbenes; Tea

Alzheimer disease (AD) is by far the most common cause of dementia globally. This neurodegenerative disorder of the brain is chronic and progressive, characterized clinically by the deterioration in the key symptoms of behavioral and cognitive abilities. Treatment options for this disease currently are limited. Deposition of amyloid-β and tau hyperphosphorylation are cardinal pathologic features of AD that lead to the formation of neuronal plaques and neurofibrillary tangles, respectively. In addition to mounting research on herbal compounds for the treatment of AD, curcuminoids and resveratrol appear to be beneficial as anti-AD agents. Curcuminoids (curcumin and demethoxycurcumin) and resveratrol possess unique properties that make them especially worthy of further studies. This review article revisits and presents the current research done on the potential of the curcuminoids curcumin and demethoxycurcumin and the polyphenolic compound resveratrol as anti-AD compounds.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Antioxidants; Curcumin; Diarylheptanoids; Humans; Male; Resveratrol; Stilbenes; tau Proteins

Curcumin, the phytochemical agent in the spice turmeric, which gives Indian curry its yellow colour, is also a traditional Indian medicine. It has been used for millennia as a wound-healing agent and for treating a variety of ailments. The antioxidant, anti-inflammatory, antiproliferative and other properties of curcumin have only recently gained the attention of modern pharmacology. The mechanism of action of curcumin is complex and multifaceted. In part, curcumin acts by activating various cytoprotective proteins that are components of the phase II response. Over the past decade, research with curcumin has increased significantly. In vitro and in vivo studies have demonstrated that curcumin could target pathways involved in the pathophysiology of Alzheimer disease (AD), such as the β-amyloid cascade, tau phosphorylation, neuroinflammation or oxidative stress. These findings suggest that curcumin might be a promising compound for the development of AD therapy. However, its insolubility in water and poor bioavailability have limited clinical trials and its therapeutic applications. To be effective as a drug therapy, curcumin must be combined with other drugs, or new delivery strategies need to be developed.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Anti-Inflammatory Agents; Antioxidants; Clinical Trials as Topic; Curcumin; Humans; Oxidative Stress

Alzheimer's disease (AD) is an age-related neurodegenerative disease increasingly recognized as one of the most important medical problems affecting the elderly. Although a number of drugs, including several cholinesterase inhibitors and an NMDA receptor antagonist, have been approved for use, they have been shown to produce diverse side effects and yield relatively modest benefits. To overcome these limitations of current therapeutics for AD, extensive research and development are underway to identify drugs that are effective and free of undesirable side effects. Certain naturally occurring dietary polyphenolic phytochemicals have received considerable recent attention as alternative candidates for AD therapy. In particular, curcumin, resveratrol, and green tea catechins have been suggested to have the potential to prevent AD because of their anti-amyloidogenic, anti-oxidative, and anti-inflammatory properties. These polyphenolic phytochemicals also activate adaptive cellular stress responses, called 'neurohormesis', and suppress disease processes. In this commentary, we describe the amyloid-beta-induced pathogenesis of AD, and summarize the intracellular and molecular targets of selected dietary phytochemicals that might slow the progression of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Catechin; Cognition Disorders; Curcumin; Dietary Supplements; Humans; Oxidative Stress; Phytotherapy; Plant Extracts; Resveratrol; Stilbenes

Morbidities of aging and Alzheimer's disease (AD) have been related to defective functions of both T cells and macrophages leading to brain amyloidosis and inflammation. In AD patients, "inflammaging" may be associated with an increase of incompetent memory T cells and inflammatory cytokines produced by macrophages, whereas defective clearance of amyloid-beta 1-42 (Abeta) may be related to defective transcription of immune genes necessary for Abeta phagocytosis, beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase and Toll-like receptors. However, AD shows considerable heterogeneity of disease manifestations and mechanisms. The approaches to re-balancing Abeta immunity and inflammation are being pursued in transgenic animal models and peripheral blood mononuclear cells of patients. The regulatory signaling pathways of microglial phagocytosis and inflammation involving co-receptors and transforming growth factor-beta have been considerably clarified in animal studies. Natural immunostimulating therapies using vitamin D3 and curcuminoids have been developed in macrophages of AD patients. AD patients possess two types of macrophages: a majority has "Type I", which are improved by curcuminoids and vitamin D3; whereas a minority has "Type II" responding positively to vitamin D3 but not to curcuminoids. Other nutritional substances, such as plant polyphenols and omega-3 fatty acids, may inhibit inflammation and stimulate immunity. More invasive immune approaches involve Abeta vaccine and cytokine antagonists. Increased inflammation may represent the "first hit", and defective transcription of immune genes the "second hit" in the pathogenesis of AD.

Topics: Adjuvants, Immunologic; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholecalciferol; Curcumin; Encephalitis; Humans; Immunity, Innate; Macrophages; Phagocytosis; Transforming Growth Factor beta

Currently, there are five anti-Alzheimer's disease drugs approved. These are tacrine, donepezil, rivastigmine, galantamine, and memantine. The mechanism of the first four drugs is acetylcholinesterase inhibition, while memantine is an NMDA-receptor antagonist. However, these drugs do not cure Alzheimer's, but are only symptomatic treatments. Therefore, a cure for Alzheimer's disease is truly needed. Alzheimer's disease is a progressive neurodegenerative disease characterized by cognitive deficits. The cause of the disease is not well understood, but research indicates that the aggregation of beta-amyloid is the fundamental cause. This theory suggests that beta-amyloid aggregation causes neurotoxicity. Therefore, development of the next anti-Alzheimer's disease drug is based on the beta-amyloid theory. We are now studying natural products, such as mulberry leaf extracts and curcumin derivatives, as potential cure for Alzheimer's disease. In this report, we describe some data about these natural products and derivatives.

Topics: Agglutination; Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Curcumin; Drug Discovery; Humans; Morus; Phytotherapy; Plant Extracts; Plant Leaves

Curcumin has a long history of use as a traditional remedy and food in Asia. Many studies have reported that curcumin has various beneficial properties, such as antioxidant, antiinflammatory, and antitumor. Because of the reported effects of curcumin on tumors, many clinical trials have been performed to elucidate curcumin's effects on cancers. Recent reports have suggested therapeutic potential of curcumin in the pathophysiology of Alzheimer's disease (AD). In in vitro studies, curcumin has been reported to inhibit amyloid-β-protein (Aβ) aggregation, and Aβ-induced inflammation, as well as the activities of β-secretase and acetylcholinesterase. In in vivo studies, oral administration of curcumin has resulted in the inhibition of Aβ deposition, Aβ oligomerization, and tau phosphorylation in the brains of AD animal models, and improvements in behavioral impairment in animal models. These findings suggest that curcumin might be one of the most promising compounds for the development of AD therapies. At present, four clinical trials concerning the effects of curcumin on AD has been conducted. Two of them that were performed in China and USA have been reported no significant differences in changes in cognitive function between placebo and curcumin groups, and no results have been reported from two other clinical studies. Additional trials are necessary to determine the clinical usefulness of curcumin in the prevention and treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Clinical Trials as Topic; Curcumin; Enzyme Inhibitors; Humans

Alzheimer's disease (AD) involves a complex pathological cascade thought to be initially triggered by the accumulation of beta-amyloid (Abeta) peptide aggregates or aberrant amyloid precursor protein (APP) processing. Much is known of the factors initiating the disease process decades prior to the onset of cognitive deficits, but an unclear understanding of events immediately preceding and precipitating cognitive decline is a major factor limiting the rapid development of adequate prevention and treatment strategies. Multiple pathways are known to contribute to cognitive deficits by disruption of neuronal signal transduction pathways involved in memory. These pathways are altered by aberrant signaling, inflammation, oxidative damage, tau pathology, neuron loss, and synapse loss. We need to develop stage-specific interventions that not only block causal events in pathogenesis (aberrant tau phosphorylation, Abeta production and accumulation, and oxidative damage), but also address damage from these pathways that will not be reversed by targeting prodromal pathways. This approach would not only focus on blocking early events in pathogenesis, but also adequately correct for loss of synapses, substrates for neuroprotective pathways (e.g., docosahexaenoic acid), defects in energy metabolism, and adverse consequences of inappropriate compensatory responses (aberrant sprouting). Monotherapy targeting early single steps in this complicated cascade may explain disappointments in trials with agents inhibiting production, clearance, or aggregation of the initiating Abeta peptide or its aggregates. Both plaque and tangle pathogenesis have already reached AD levels in the more vulnerable brain regions during the "prodromal" period prior to conversion to "mild cognitive impairment (MCI)." Furthermore, many of the pathological events are no longer proceeding in series, but are going on in parallel. By the MCI stage, we stand a greater chance of success by considering pleiotropic drugs or cocktails that can independently limit the parallel steps of the AD cascade at all stages, but that do not completely inhibit the constitutive normal functions of these pathways. Based on this hypothesis, efforts in our laboratories have focused on the pleiotropic activities of omega-3 fatty acids and the anti-inflammatory, antioxidant, and anti-amyloid activity of curcumin in multiple models that cover many steps of the AD pathogenic cascade (Cole and Frautschy, Alzheimers Dement 2:284-

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Curcumin; Docosahexaenoic Acids; Down Syndrome; Energy Metabolism; Enzyme Inhibitors; Humans; Peptide Fragments; Signal Transduction; tau Proteins

Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly. Deposition of amyloid beta plaque and associated neuroinflammation are the major hallmarks of AD. Whereas reactive oxygen species (ROS) and activated microglial cells contribute to neuronal loss, nuclear factor kappaB and apolipoprotein E participate in inflammatory process of AD. Current FDA approved drugs provide only symptomatic relief in AD. For broad spectrum of activity, some natural products are also being tested. Turmeric is used as an anti-inflammatory medicine in various regions of Asia. Curcumin, which is a yellow colored polyphenol compound present in turmeric, showed anti-inflammatory properties. Herein, we discuss the neurobiological and neuroinflammatory pathways of AD, evaluate different molecular targets and potential therapeutic agents, including curcumin, for the treatment of AD.

Topics: Alzheimer Disease; Animals; Curcumin; Drug Delivery Systems; Humans; Inflammation Mediators; Neurogenic Inflammation; Neuroimmunomodulation

Traditionally, turmeric has been put to use as a food additive and herbal medicine in Asia. Curcumin is an active principle of the perennial herb curcuma longa (commonly known as turmeric). Recent evidence suggests that curcumin has activities with potential for neuroprotective efficacy, including anti-inflammatory, antioxidant, and antiprotein-aggregate activities. In the current review, we provide the newly evidence for the potential role of curcumin in the neuroprotective effects of neurodegenerative diseases like Alzheimer's disease (AD).

Topics: Alzheimer Disease; Animals; Curcuma; Curcumin; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Plant Extracts

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of intracellular and extracellular aggregates. According to the amyloid beta (Abeta) hypothesis, amyloidosis occurring in the brain is a leading cause of neurodegeneration in AD. Defects in the innate immune system may decrease the clearance of Abeta in the brain. Macrophages of most AD patients do not transport Abeta into endosomes and lysosomes, and monocytes from AD patients do not efficiently clear Abeta from AD brain. After stimulation with Abeta, mononuclear cells of normal subjects display up-regulated transcription of MGAT3, which encodes beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase, and Toll-like receptor (TLR) genes. Monocytes of AD patients generally down-regulate these genes. A commonly used, naturally occurring material from a spice that enhances certain key functions defective in cells of innate immunity of many AD patients has shown epidemiologic rationale for use in AD treatment. Bisdemethoxycurcumin, a natural curcumin, is a minor constituent of turmeric (curry), and it enhances phagocytosis and clearance of Abeta in cells from most AD patients. We confirmed the effectiveness of a synthetic version of the same compound. In mononuclear cells of most AD patients, bisdemethoxycurcumin enhanced defective phagocytosis of Abeta and increased the transcription of MGAT3 and TLR genes. The potency of bisdemethoxycurcumin as a highly purified compound in facilitating the clearance of Abeta in mononuclear cells suggests the promise of enhanced effectiveness compared to curcuminoid mixtures. Bisdemethoxycurcumin appears to enhance immune function in mononuclear cells of AD patients and may provide a novel approach to AD immunotherapy.

Topics: Acyltransferases; Alzheimer Disease; Amyloid beta-Peptides; Animals; Curcumin; Diarylheptanoids; Humans; Immunity, Innate; Leukocytes, Mononuclear; Models, Biological; Toll-Like Receptors

There is a growing body of evidence to support a role for oxidative stress in Alzheimer's disease (AD), with increased levels of lipid peroxidation, DNA and protein oxidation products (HNE, 8-HO-guanidine and protein carbonyls respectively) in AD brains. The brain is a highly oxidative organ consuming 20% of the body's oxygen despite accounting for only 2% of the total body weight. With normal ageing the brain accumulates metals ions such iron (Fe), zinc (Zn) and copper (Cu). Consequently the brain is abundant in antioxidants to control and prevent the detrimental formation of reactive oxygen species (ROS) generated via Fenton chemistry involving redox active metal ion reduction and activation of molecular oxygen. In AD there is an over accumulation of the Amyloid beta peptide (Abeta), this is the result of either an elevated generation from amyloid precursor protein (APP) or inefficient clearance of Abeta from the brain. Abeta can efficiently generate reactive oxygen species in the presence of the transition metals copper and iron in vitro. Under oxidative conditions Abeta will form stable dityrosine cross-linked dimers which are generated from free radical attack on the tyrosine residue at position 10. There are elevated levels of urea and SDS resistant stable linked Abeta oligomers as well as dityrosine cross-linked peptides and proteins in AD brain. Since soluble Abeta levels correlate best with the degree of degeneration [C.A. McLean, R.A. Cherny, F.W. Fraser, S.J. Fuller, M.J. Smith, K. Beyreuther, A.I. Bush, C.L. Masters, Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease, Ann. Neurol. 46 (1999) 860-866] we suggest that the toxic Abeta species corresponds to a soluble dityrosine cross-linked oligomer. Current therapeutic strategies using metal chelators such as clioquinol and desferrioxamine have had some success in altering the progression of AD symptoms. Similarly, natural antioxidants curcumin and ginkgo extract have modest but positive effects in slowing AD development. Therefore, drugs that target the oxidative pathways in AD could have genuine therapeutic efficacy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Chelating Agents; Curcumin; DNA; Enzyme Inhibitors; Ginkgo biloba; Humans; Lipid Peroxidation; Metals; Oxidation-Reduction; Oxygen; Oxygen Consumption; Peptides; Plant Extracts; Reactive Oxygen Species; Tyrosine

Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. A large body of evidence indicates that oxidative stress is involved in the pathophysiology of these diseases. Oxidative stress can induce neuronal damages, modulate intracellular signaling, ultimately leading to neuronal death by apoptosis or necrosis. Thus antioxidants have been studied for their effectiveness in reducing these deleterious effects and neuronal death in many in vitro and in vivo studies. Increasing number of studies demonstrated the efficacy of polyphenolic antioxidants from fruits and vegetables to reduce or to block neuronal death occurring in the pathophysiology of these disorders. These studies revealed that other mechanisms than the antioxidant activities could be involved in the neuroprotective effect of these phenolic compounds. We will review some of these mechanisms and particular emphasis will be given to polyphenolic compounds from green tea, the Ginkgo biloba extract EGb 761, blueberries extracts, wine components and curcumin.

Topics: Alzheimer Disease; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Blueberry Plants; Clinical Trials as Topic; Cognition; Curcumin; Flavonoids; Ginkgo biloba; Humans; Neurodegenerative Diseases; Parkinson Disease; Phenols; Plant Extracts; Polyphenols; Proteasome Endopeptidase Complex; Resveratrol; Signal Transduction; Stilbenes; Tea; Wine

There is substantial in-vitro data indicating that curcumin has antioxidant, anti-inflammatory, and anti-amyloid activity. In addition, studies in animal models of Alzheimer's disease (AD) indicate a direct effect of curcumin in decreasing the amyloid pathology of AD. As the widespread use of curcumin as a food additive and relatively small short-term studies in humans suggest safety, curcumin is a promising agent in the treatment and/or prevention of AD. Nonetheless, important information regarding curcumin bioavailability, safety and tolerability, particularly in an elderly population is lacking. We are therefore performing a study of curcumin in patients with AD to gather this information in addition to data on the effect of curcumin on biomarkers of AD pathology.

Topics: Alzheimer Disease; Animals; Clinical Trials, Phase II as Topic; Curcuma; Curcumin; Humans; Phytotherapy; Spices

Alzheimer's disease (AD) and cardiovascular disease (CVD) are syndromes of aging that share analogous lesions and risk factors, involving lipoproteins, oxidative damage and inflammation. Unlike in CVD, in AD, sensitive biomarkers are unknown, and high-risk groups are understudied. To identify potential prevention strategies in AD, we have focused on pre-clinical models (transgenic and amyloid infusion models), testing dietary/lifestyle factors strongly implicated in reducing risk in epidemiological studies. Initially, we reported the impact of non-steroidal anti-inflammatory drugs (NSAIDs), notably ibuprofen, which reduced amyloid accumulation, but suppressed few inflammatory markers and without reducing oxidative damage. Safety concerns with chronic NSAIDs led to a screen of alternative NSAIDs and identification of the phenolic anti-inflammatory/anti-oxidant compound curcumin, the yellow pigment in turmeric that we found targeted multiple AD pathogenic cascades. The dietary omega-3 fatty acid, docosahexaenoic acid (DHA), also limited amyloid, oxidative damage and synaptic and cognitive deficits in a transgenic mouse model. Both DHA and curcumin have favorable safety profiles, epidemiology and efficacy, and may exert general anti-aging benefits (anti-cancer and cardioprotective.).

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Curcumin; Fatty Acids, Omega-3; Flavonoids; Humans; Phenols; Polyphenols

Cognitive impairment develops with pre-diabetes and dementia is a complication of diabetes. Natural products like turmeric and cinnamon may ameliorate the underlying pathogenesis.. People ≥ 60 years (n=48) with newly-recognised untreated pre-diabetes were randomised to a double-blind metabolic study of placebo, turmeric (1 g), cinnamon (2 g) or both (1 g & 2 g respectively), ingested at a white bread (119 g) breakfast. Observations were made over 6 hours for pre- and post-working memory (WM), glycaemic and insulin responses and biomarkers of Alzheimer's disease (AD)(0, 2, 4 and 6 hours): amyloid precursor protein (APP), γ-secretase subunits presenilin-1 (PS1), presenilin-2 (PS2), and glycogen synthase kinase (GSK-3β). Differences between natural product users and non-users were determined by Students t and chi square tests; and between pre-test and post-test WM by Wilcoxon signed rank tests. Interaction between turmeric and cinnamon was tested by 2-way ANOVA. Multivariable linear regression (MLR) took account of BMI, glycaemia, insulin and AD biomarkers in the WM responses to turmeric and cinnamon.. No interaction between turmeric and cinnamon was detected. WM increased from 2.6 to 2.9 out of 3.0 (p=0.05) with turmeric, but was unchanged with cinnamon. WM improvement was inversely associated with insulin resistance (r=-0.418, p<0.01), but not with AD biomarkers. With MLR, the WM responses to turmeric were best predicted with an R2 of 34.5%; and with significant turmeric, BMI and insulin/glucose AUC beta-coefficients.. Co-ingestion of turmeric with white bread increases working memory independent of body fatness, glycaemia, insulin, or AD biomarkers.. 背景：認知功能失調伴隨糖尿病前期與失智症是糖尿病的併發症之ㄧ。天然食品如薑黃及 肉桂可改善此致病機轉。本研究為評估薑黃肉桂如何影響糖尿病前期患者認知功能之代謝 研究。方法：對象為三軍總醫院參加老人健檢者，納入條件為其空腹血糖介於100-126 mg/dL，共計48 位參與者。經由雙盲性別分層隨機分派至服用口服降血糖藥物或其組合、 薑黃、肉桂或其組合及控制組共4 組，每組12 名，男女各半。參與者須於報到後抽取空 腹血液、實施工作記憶前測及測量基本體位資料。再於8 時服用早餐及受試藥物，各組分 別為安慰劑、薑黃1 克、肉桂2 克、肉桂2 克與薑黃1 克等。隨後每隔2 小時採集血液， 共4 次，於最後1 次抽血完畢後，再測工作記憶分數。利用RT-PCR 技術測得APP、 PS1、PS2、GSK-3βmRNA 表現量。利用t 檢定及卡方檢定比較天然食品使用者及非使用 者平均值之差異；魏克森符號等級檢定工作記憶前測及後測的分數。利用雙因子變異數分 析檢定薑黃與肉桂兩植物成分之交互作用。複迴歸模式分析校正身體質量指數、血糖、胰 島素濃度、阿茲海默症相關之生物標記後，薑黃肉桂對工作記憶之影響。結果：薑黃與肉 桂兩植物成分並無交互作用產生。有服用薑黃者工作記憶平均分數由2.6 增加至2.9 分， 為邊緣性顯著（p=0.05），服用肉桂者工作記憶前後測平均分數沒有顯著差異。工作記憶 分數之改善與胰島素阻抗呈負相關 （r=-0.418, p<0.01），但與阿茲海默症之相關生物標記 無顯著相關。複迴歸分析結果顯示服用薑黃、BMI 及胰島素阻抗為工作記憶分數最佳預測 因子。結論：本研究觀察到的薑黃改善認知效果，可能並非透過假設之降血糖途徑或降低 生物標記基因表現量而來，推測薑黃有其他保護神經元機制。

Topics: Aged; Alzheimer Disease; Biomarkers; Blood Glucose; Body Mass Index; Bread; Cinnamomum zeylanicum; Curcuma; Double-Blind Method; Female; Humans; Insulin; Insulin Resistance; Male; Memory; Middle Aged; Phytotherapy; Placebos; Plant Preparations; Postprandial Period; Prediabetic State

Curcumin extracts of turmeric are proposed to produce health benefits. To date, human intervention studies have focused mainly on people with existing health problems given high doses of poorly absorbed curcumin. The purpose of the current study was to check whether in healthy people, a low dose of a lipidated curcumin extract could alter wellness-related measures.. The present study was conducted in healthy middle aged people (40-60 years old) with a low dose of curcumin (80 mg/day) in a lipidated form expected to have good absorption. Subjects were given either curcumin (N = 19) or placebo (N = 19) for 4 wk. Blood and saliva samples were taken before and after the 4 weeks and analyzed for a variety of blood and saliva measures relevant to health promotion.. Curcumin, but not placebo, produced the following statistically significant changes: lowering of plasma triglyceride values, lowering of salivary amylase levels, raising of salivary radical scavenging capacities, raising of plasma catalase activities, lowering of plasma beta amyloid protein concentrations, lowering of plasma sICAM readings, increased plasma myeloperoxidase without increased c-reactive protein levels, increased plasma nitric oxide, and decreased plasma alanine amino transferase activities.. Collectively, these results demonstrate that a low dose of a curcumin-lipid preparation can produce a variety of potentially health promoting effects in healthy middle aged people.

Topics: Adult; Aging; Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Cardiovascular Diseases; Curcuma; Curcumin; Dietary Supplements; Female; Humans; Hypertriglyceridemia; Lipids; Male; Middle Aged; Ohio; Plant Extracts; Plant Roots; Risk; Stress, Psychological

Patients with Alzheimer's disease (AD) suffer from brain amyloidosis related to defective clearance of amyloid-beta (Abeta) by the innate immune system. To improve the innate immune system of AD patients, we studied immune stimulation of macrophages by 1alpha,25(OH)2-vitamin D3(1,25D3) in combination with curcuminoids. AD patients' macrophages segregate into Type I (positively stimulated by curcuminoids regarding MGAT-III transcription) and Type II (not stimulated). In both Type I and Type II macrophages, 1,25D3 strongly stimulated Abeta phagocytosis and clearance while protecting against apoptosis. Certain synthetic curcuminoids in combination with 1,25D3 had additive effects on phagocytosis in Type I but not Type II macrophages. In addition, we investigated the mechanisms of 1,25D3 and curcuminoids in macrophages. The 1,25D3 genomic antagonist analog MK inhibited 1,25D3 but not curcuminoid effects, suggesting that 1,25D3 acts through the genomic pathway. In silico, 1,25D3 showed preferential binding to the genomic pocket of the vitamin D receptor, whereas bisdemethoxycurcumin showed preference for the non-genomic pocket. 1,25D3 is a promising hormone for AD immunoprophylaxis because in Type I macrophages combined treatment with 1,25D3 and curcuminoids has additive effects, and in Type II macrophages 1,25D3 treatment is effective alone. Human macrophages are a new paradigm for testing immune therapies for AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cells, Cultured; Cholecalciferol; Cognition Disorders; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Drug Interactions; Female; Gene Expression Regulation; Humans; Liver; Macrophages; Male; Middle Aged; N-Acetylglucosaminyltransferases; Peptide Fragments; Phagocytosis; Protein Structure, Tertiary; Receptors, Calcitriol; Time Factors; Toll-Like Receptor 1; Transfection

Topics: Aged; Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Asian People; Capsules; Curcuma; Curcumin; Double-Blind Method; Female; Hong Kong; Humans; Male; Phytotherapy; Pilot Projects

Studies in animals and a short-term human study have suggested that curcumin, a polyphenolic compound concentrated in the curry spice turmeric, decreases serum cholesterol concentration. However, no controlled human trials have examined the effect of curcumin on cholesterol. This study investigated the effects of consuming curcumin on the serum lipid profile in men and women. Elderly subjects (n=36) consumed 4 g/d curcumin, 1g/d curcumin, or placebo in a 6-month, randomized, double-blind trial. Plasma curcumin and its metabolites were measured at 1 month, and the serum lipid profile was measured at baseline, 1 month, and 6 months. The plasma curcumin concentration reached a mean of 490 nmol/L. The curcumin concentration was greater after capsule than powder administration. Consumption of either dose of curcumin did not significantly affect triacylglycerols, or total, LDL, and HDL cholesterol over 1 month or 6 months. However, the concentrations of plasma curcumin and serum cholesterol were positively and significantly correlated. Curcumin consumption does not appear to have a significant effect on the serum lipid profile, unless the absorbed concentration of curcumin is considered, in which case curcumin may modestly increase cholesterol.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholesterol; Curcumin; Double-Blind Method; Female; Humans; Male; Middle Aged; Triglycerides

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Curcumin; Humans

Alzheimer's disease (AD) is one of the most common causes of dementia, affecting many old people.. By designing and synthesizing intracerebral imaging probes, we tried to provide a new solution for the early diagnosis of AD.. We designed and synthesized bis-iodine-labeled curcumin, and verified its performance through in vivo and in vitro experiments.. All results suggested that BICUR could probably act as a targeted CT imaging agent for Aβ plaques in the brain.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Curcumin; Iodine; Mice; Mice, Transgenic; Plaque, Amyloid; Tissue Distribution; Tomography, X-Ray Computed

Kalyanaka ghrita (KG) is an Ayurvedic formulation traditionally used in the treatment of Daurbalya (debility) and Smritidaurbalya (impairment of intellectual activities). Clinical studies have reported the effect of KG in the treatment of Manasmandata or Buddhimandyata which is associated with impaired learning, social adjustment and maturation.. The present study aims to standardization of KG and validation of its use in experimental models of neurodegeneration.. KG was Standardized for biomarkers curcumin, gallic acid, tannic acid, chebulagic acid, and berberine. In male wistar rats, neurodegeneration was induced by administration of intracerebroventricular Amyloid β (Aβ. A novel HPLC method has been developed for the standardization of KG. Treatment with KG significantly improved cognition and memory and increased brain BDNF and antioxidant status in Aβ. The findings suggest that KG has neuroprotective potential and along with its nootropic property could be a promising therapy for neurodegenerative diseases like Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Berberine; Brain-Derived Neurotrophic Factor; Curcumin; Cytokines; Disease Models, Animal; Male; Maze Learning; Memory Disorders; Neuroprotective Agents; Nootropic Agents; Rats; Rats, Wistar; Tannins

Tau is a natively unfolded microtubule-associated protein. Tau neurofibrillary tangles are one of the hallmarks of Alzheimer's disease. The post-translational modifications of Tau lead to its pathological state. Phosphorylation is the key post-translational modification associated with Tauopathy. Curcumin is a polyphenolic compound present in the rhizomes of Curcuma longa. Curcumin has been reported to have remarkable medicinal properties in several diseases, but its poor solubility limits its therapeutic potency. Artemisinin is a sesquiterpene lactone, which has been known sience ancient times for its applications as a treatment for various diseases such as malaria, cancer, autoimmune disease, etc. In the present study, the potency of crystalline curcumin, crystalline artemisinin, and Cur-Art co-amorphous dispersion were evaluated against Tau pathology. The in-vitro ThS/ANS fluorescence and electron microscopy results suggested that curcumin and Cur-Art efficiently inhibited Tau aggregation. Furthermore, exposure to curcumin and Cur-Art co-amorphous restored the impaired nuclear transport in formaldehyde-stressed cells. Curcumin was also found to modulate the phosphorylation of Tau, which indicated the neuroprotective potency. Thus, curcumin and Cur-Art co-amorphous exhibit therapeutic potential against Tau protein in Alzheimer's disease.

Topics: Alzheimer Disease; Artemisinins; Curcumin; Humans; Phosphorylation; tau Proteins

Curcumin (CUR) and piperine (PIP) are very well-known phytochemicals that claimed to have many health benefits and have been widely used in foods and traditional medicines. This study investigated the therapeutic efficacy of these compounds to treat Alzheimer's disease (AD). However, poor oral bioavailability and permeability of curcumin are a major challenge for formulation scientists. In this research study, the researcher tried to enhance the bioavailability and permeability of curcumin by a nanotechnological approach. In this research study, we developed a CUR-PIP-loaded SNEDDS in various oils. Optimised formulation NF3 was subjected to evaluate its therapeutic effectiveness on AD animal model in comparison with untreated AD model and treated group (by market formulation donepezil). On the basis of characterisation results, it is confirmed that NF3 formulation is the best formulation. The optimised formulation shows a significant dose-dependent manner therapeutic effect on AD-induced model. Novel formulation CUR-PIP solid-SNEDDS was successfully developed and optimised. It is expected that the developed S-SNEDDS can be a potential, safe and effective carrier for the oral delivery of curcumin to the brain. To date, this article is the only study of CUR-PIP-loaded S-SNEDDS for the treatment of AD.

Topics: Alzheimer Disease; Animals; Biological Availability; Curcumin; Drug Delivery Systems; Emulsions; Nanoparticles; Particle Size; Piperidines

Curcumin is a natural anti-inflammatory and antioxidant substance which plays a major role in reducing the amyloid plaques formation, which is the major cause of Alzheimer's disease (AD). Consequently, a methodical approach was used to select the potential protein targets of curcumin in AD through network pharmacology. In this study, through integrative methods, AD targets of curcumin through SwissTargetPrediction database, STITCH database, BindingDB, PharmMapper, Therapeutic Target Database (TTD), Online Mendelian Inheritance in Man (OMIM) database were predicted followed by gene enrichment analysis, network construction, network topology, and docking studies. Gene ontology analysis facilitated identification of a list of possible AD targets of curcumin (74 targets genes). The correlation of the obtained targets with AD was analysed by using gene ontology (GO) pathway enrichment analyses and Kyoto Encyclopaedia of Genes and Genomes (KEGG). We have incorporated the applied network pharmacological approach to identify key genes. Furthermore, we have performed molecular docking for analysing the mechanism of curcumin. In order to validate the temporospatial expression of key genes in human central nervous system (CNS), we searched the Human Brain Transcriptome (HBT) dataset. We identified top five key genes namely, PPARγ, MAPK1, STAT3, KDR and APP. Further validated the expression profiling of these key genes in publicly available brain data expression profile databases. In context to a valuable addition in the treatment of AD, this study is concluded with novel insights into the therapeutic mechanisms of curcumin, will ease the treatment of AD with the clinical application of curcumin.

Topics: Alzheimer Disease; Computational Biology; Curcumin; Databases, Genetic; Humans; Molecular Docking Simulation; Network Pharmacology

In Alzheimer's disease (AD), accumulation of amyloid β-protein (Aβ) is one of the major mechanisms causing neuronal cell damage. Disruption of cell membranes by Aβ has been hypothesized to be the important event associated with neurotoxicity in AD. Curcumin has been shown to reduce Aβ-induced toxicity; however, due to its low bioavailability, clinical trials showed no remarkable effect on cognitive function. As a result, GT863, a derivative of curcumin with higher bioavailability, was synthesized. The purpose of this study is to clarify the mechanism of the protective action of GT863 against the neurotoxicity of highly toxic Aβ oligomers (Aβo), which include high-molecular-weight (HMW) Aβo, mainly composed of protofibrils in human neuroblastoma SH-SY5Y cells, focusing on the cell membrane. The effect of GT863 (1 μM) on Aβo-induced membrane damage was assessed by phospholipid peroxidation of the membrane, membrane fluidity, membrane phase state, membrane potential, membrane resistance, and changes in intracellular Ca

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Membrane; Curcumin; Humans; Neuroblastoma; Phospholipids

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative illnesses, and yet, no workable treatments have been discovered to prevent or reverse AD. Curcumin (CUR), the major polyphenolic compound of turmeric (Curcuma longa) rhizomes, and Ginkgo biloba extract (GBE) are natural substances derived from conventional Chinese herbs that have long been shown to provide therapeutic advantages for AD. The uptake of curcumin into the brain is severely restricted by its low ability to cross the blood-brain barrier (BBB). Meanwhile, GBE has been shown to improve BBB permeability. The present study evaluated the neuroprotective effects and pharmacokinetic profile of curcumin and GBE combination to find out whether GBE can enhance curcumin's beneficial effects in AD by raising its brain concentration. Results revealed that CUR + GBE achieved significantly higher levels of curcumin in the brain and plasma after 30 min and 1 h of oral administration, compared to curcumin alone, and this was confirmed by reversed phase high-performance liquid chromatography (RP-HPLC). The effect of combined oral treatment, for 28 successive days, on cognitive function and other AD-like alterations was studied in scopolamine-heavy metal mixtures (SCO + HMM) AD model in rats. The combination reversed at least, partially on the learning and memory impairment induced by SCO + HMM. This was associated with a more pronounced inhibitory effect on acetylcholinesterase (AChE), caspase-3, hippocampal amyloid beta (Aβ1-42), and phosphorylated tau protein (p-tau) count, and pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukine-1beta (IL-1β), as compared to the curcumin alone-treated group. Additionally, the combined treatment significantly decreased lipid peroxidation (MDA) and increased levels of reduced glutathione (GSH), when compared with the curcumin alone. These findings support the concept that the combination strategy might be an alternative therapy in the management/prevention of neurological disorders. This study sheds light on a new approach for exploring new phyto-therapies for AD and emphasizes that more research should focus on the synergic effects of herbal drugs in future.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Curcumin; Neuroprotective Agents; Plant Extracts; Rats

Simultaneous modulation of multifaceted toxicity arising from neuroinflammation, oxidative stress, and mitochondrial dysfunction represents a valuable therapeutic strategy to tackle Alzheimer's disease. Among the significant hallmarks of the disorder, Aβ protein and its aggregation products are well-recognised triggers of the neurotoxic cascade. In this study, by tailored modification of the curcumin-based lead compound 1, we aimed at developing a small library of hybrid compounds targeting Aβ protein oligomerisation and the consequent neurotoxic events. Interestingly, from in vitro studies, analogues 3 and 4, bearing a substituted triazole moiety, emerged as multifunctional agents able to counteract Aβ aggregation, neuroinflammation and oxidative stress. In vivo proof-of-concept evaluations, performed in a Drosophila oxidative stress model, allowed us to identify compound 4 as a promising lead candidate.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Curcumin; Humans; Neuroinflammatory Diseases; Oxidative Stress

Neuronal damage caused by β-amyloid (Aβ) aggregates and excess reactive oxygen species (ROS) is a crucial pathogenic event in Alzheimer's disease (AD). However, current Aβ-targeting RNA interference (RNAi) treatments have shown limited therapeutic efficacy due to ineffective intracerebral siRNA delivery and overlooked crosstalk between excess ROS and Aβ aggregates in the brain. Herein, a ROS-responsive nanomodulator (NM/CM) was developed for the combinational treatment of RNAi and ROS elimination for AD. NM/CM was coated with 4T1 cell membranes, which endowed NM/CM with the capability to cross blood-brain barrier (BBB). After being internalized by neural cells, NM/CM releases curcumin (Cur) and siIFITM3 spontaneously into the cytoplasm. The released Cur can eliminate ROS, protecting neurons from oxidative damage and reducing the production of Aβ induced by ROS-related neuroinflammation. The released siIFITM3 can downregulate the expression of interferon-induced transmembrane protein 3 (IFITM3), thereby reducing the abnormal Aβ production mediated by IFITM3. As a result, NM/CM remarkably alleviated ROS- and Aβ aggregate-induced neurotoxicity in vitro, showing significant neuroprotective effects. This work demonstrates the potential of NM/CM in the development of novel and effective AD combination therapies.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Blood-Brain Barrier; Curcumin; Humans; Membrane Proteins; Oxidative Stress; Reactive Oxygen Species; RNA-Binding Proteins

Alzheimer's disease is a neurologic disorder characterized by the accumulation of extracellular deposits of amyloid-β (Aβ) fibrils in the brain of patients. The key etiologic agent in Alzheimer's disease is not known; however oligomeric Aβ appears detrimental to neuronal functions and increases Aβ fibrils deposition. Previous research has shown that curcumin, a phenolic pigment of turmeric, has an effect on Aβ assemblies, although the mechanism remains unclear. In this study, we demonstrate that curcumin disassembles pentameric oligomers made from synthetic Aβ42 peptides (pentameric oAβ42), using atomic force microscopy imaging followed by Gaussian analysis. Since curcumin shows keto-enol structural isomerism (tautomerism), the effect of keto-enol tautomerism on its disassembly was investigated. We have found that curcumin derivatives capable of keto-enol tautomerization also disassemble pentameric oAβ42, while, a curcumin derivative incapable of tautomerization did not affect the integrity of pentameric oAβ42. These experimental findings indicate that keto-enol tautomerism plays an essential role in the disassembly. We propose a mechanism for oAβ42 disassembly by curcumin based on molecular dynamics calculations of the tautomerism. When curcumin and its derivatives bind to the hydrophobic regions of oAβ42, the keto-form changes predominantly to the enol-form; this transition is associated with structural (twisting, planarization and rigidification) and potential energy changes that give curcumin enough force to act as a torsion molecular-spring that eventually disassembles pentameric oAβ42. This proposed mechanism sheds new light on keto-enol tautomerism as a relevant chemical feature for designing such novel therapeutic drugs that target protein aggregation.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Brain; Curcumin; Humans; Peptide Fragments

The abnormal accumulation of amyloid β protein (Aβ) is one of the most important causes of Alzheimer's disease (AD) and is usually a detecting biomarker. Curcumin and its derivatives have potential Aβ aggregate targeting ability; we synthesized a series of curcumin-based near-infrared fluorescence probes in this study. By characterizing the excitation wavelength and emission wavelength, the imaging characteristics of the investigation in the near-infrared light region were determined; with an increase in the concentration of the probe compounds, the fluorescence intensity showed an upward trend, demonstrating ideal optical characteristics. In vivo, imaging results showed that the synthesized probe compounds could penetrate the blood-brain barrier (BBB) and specifically bind to Aβ in the brain of APP/PS1 mice. Especially for compound 3b, the maximum emission wavelength was around 667 nm, and the fluorescence signal intensity in the brain of the APP/PS1 mice model was more than twice that of the wild control group at 120 min after administration, which could display Aβ pathological changes. The fluorescent probes designed in this study can become an effective tool for early AD diagnosis and visual detection.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Curcumin; Disease Models, Animal; Fluorescent Dyes; Mice; Mice, Transgenic; Plaque, Amyloid

This study examined the effect of curcumin on pathological manifestations and clearance of amyloid β peptide (Aβ) in the hippocampus of 8-month-old transgenic APP/PS1 mice with inherent Alzheimer's disease. APP/PS1 mice and the age-matched wild-type controls were subjected to 3 behavioral tests: open field, new object recognition, and Morris water maze. Expression of Aβ, APP, CTF, BACE1, IDE, NEP, and LRP1 proteins in the extracted hippocampal tissue was evaluated by Western blotting. The distribution and the quantity of amyloid plaques and the spread of microglia in the hippocampus were determined by immunofluorescence. The contents of Aβ40 and Aβ42 in the hippocampus were assayed and analyzed on Simoa HD-1 analyzer. The proteins interacting with Aβ in the hippocampus of APP/PS1 mice were detected by co-immunoprecipitation. Curcumin significantly reduced motor hyperactivity in the open-field test, improved short-term recognition memory, spatial learning, and reference memory in APP/PS1 mice. In the hippocampus of APP/PS1 mice, curcumin significantly diminished the elevated Aβ levels and inhibited microglia proliferation. At the same time, curcumin had no effect on Aβ production, extracellular enzymatic hydrolysis, and LRP1-mediated outward transport, but enhanced Aβ clearance by activation of the intracellular ubiquitin-proteasome system and related peripheral mechanisms. Thus, curcumin improves the learning and memory abilities of APP/PS1 mice and reduces the pathological accumulation of Aβ in the brain.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Cognition; Curcumin; Hippocampus; Male; Mice; Mice, Transgenic

The development of Alzheimer's disease (AD) drugs has recently witnessed substantial achievement. To further enhance the pool of drug candidates, it is crucial to explore non-traditional therapeutic avenues. In this study, we present the use of a photolabile curcumin-diazirine analogue, CRANAD-147, to induce changes in properties, structures (sequences), and neurotoxicity of amyloid beta (Aβ) species both in cells and in vivo. This manipulation was achieved through irradiation with LED light or molecularly generated light, dubbed as "molecular light", emitted by the chemiluminescence probe ADLumin-4. Next, aided by molecular chemiluminescence imaging, we demonstrated that the combination of CRANAD-147/LED or CRANAD-147/ADLumin-4 (molecular light) could effectively slow down the accumulation of Aβs in transgenic 5xFAD mice in vivo. Leveraging the remarkable tissue penetration capacity of molecular light, phototherapy employing the synergistic effect of a photolabile Aβ ligand and molecular light emerges as a promising alternative to conventional AD treatment interventions.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Curcumin; Diazomethane; Disease Models, Animal; Mice; Mice, Transgenic; Phototherapy

Many neurodegenerative diseases involve amyloidogenic proteins forming surface-bound aggregates on anionic membranes, and the peptide amyloid β (Aβ) in Alzheimer's disease is one prominent example of this. Curcumin is a small polyphenolic molecule that provides an interesting opportunity to understand the fundamental mechanisms of membrane-mediated aggregation because it embeds into membranes to alter their structure while also altering Aβ aggregation in an aqueous environment. The purpose of this work was to understand interactions among curcumin, β-sheet-rich Aβ fibrillar oligomers (FO), and a model anionic membrane. From a combination of liquid surface X-ray scattering experiments and molecular dynamics simulations, we found that curcumin embedded into an anionic 1,2-dimyristoyl-

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Curcumin; Humans; Molecular Dynamics Simulation

A library of

Topics: Acetylcholinesterase; Alzheimer Disease; Antioxidants; Cholinesterase Inhibitors; Curcumin; Donepezil; Humans; Molecular Docking Simulation; Pain; Structure-Activity Relationship

On the basis of our previous work, a novel series of (4-(1,2,4-oxadiazol-5-yl)phenyl)-2-aminoacetamide derivatives were synthesized and evaluated as multifunctional ligands for the treatment of Alzheimer's disease (AD). Biological evaluations indicated that the derivatives can be used as anti-AD drugs that have multifunctional properties, inhibit the activity of butyrylcholinesterase (BuChE), inhibit neuroinflammation, have neuroprotective properties, and inhibit the self-aggregation of Aβ. Compound f9 showed good potency in BuChE inhibition (IC

Topics: Acetamides; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Biphenyl Compounds; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Molecular Structure; Neuroprotective Agents; Oxadiazoles; Picrates; Protein Aggregates; Structure-Activity Relationship

In this study, we designed, synthesized, and evaluated a series of carbamate derivatives of N-salicyloyl tryptamine as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). After screening the acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitory activities, target compound 1g stood out as a mixed type reversible dual inhibitor of AChE and BChE. In addition, molecular docking studies were conducted to explore the actions on AChE and BChE. The results showed that 1g could decrease the level of pro-inflammatory cytokines NO, iNOS, IL-6, TNF-α, and ROS, increase the level of anti-inflammatory cytokines IL-4, and inhibit the aggregation of Aβ

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Binding Sites; Blood-Brain Barrier; Butyrylcholinesterase; Carbamates; Cholinesterase Inhibitors; Drug Design; Humans; Male; Maze Learning; Molecular Docking Simulation; Neuroprotective Agents; Protein Aggregates; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Tryptamines

Based on multitarget-directed ligands approach, through two rounds of screening, a series of 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives were designed, synthesized and evaluated as innovative multifunctional agents against Alzheimer's disease. In vitro biological assays indicated that most of the hybrids were endowed with great AChE inhibitory activity, excellent antioxidant activity and moderate Aβ

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Cholinesterase Inhibitors; Drug Design; Mice; Protein Aggregates; Structure-Activity Relationship

In this work, a series of naringenin-O-carbamate derivatives was designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD) through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c showed good antioxidant potency (ORAC = 1.0 eq), and it was a reversible huAChE (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Butyrylcholinesterase; Carbamates; Cell Line; Cell Survival; Cholinesterase Inhibitors; Copper; Dose-Response Relationship, Drug; Drug Development; Flavanones; Humans; Molecular Structure; Neuroprotective Agents; Peptide Fragments; Protein Aggregates; Rats; Structure-Activity Relationship

A series of novel 5-hydroxyl-1-azabenzanthrone derivatives were designed, synthesized and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The most effective Compound 16 showed selective inhibition of acetylcholinesterase (eeAChE IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Binding Sites; Blood-Brain Barrier; Cholinesterase Inhibitors; Drug Design; Rats

Alzheimer's disease (AD) is a progressive neurodegenerative disease with a multifactorial etiology. A multitarget treatment that modulates multifaceted biological functions might be more effective than a single-target approach. Here, the therapeutic efficacy of combination treatment using anti-Aβ antibody NP106 and curcumin analog TML-6 versus monotherapy was investigated in an APP/PS1 mouse model of AD. Our data demonstrate that both combination treatment and monotherapy attenuated brain Aβ and improved the nesting behavioral deficit to varying degrees. Importantly, the combination treatment group had the lowest Aβ levels, and insoluble forms of Aβ were reduced most effectively. The nesting performance of APP/PS1 mice receiving combination treatment was better than that of other APP/PS1 groups. Further findings indicate that enhanced microglial Aβ phagocytosis and lower levels of proinflammatory cytokines were concurrent with the aforementioned effects of NP106 in combination with TML-6. Intriguingly, combination treatment also normalized the gut microbiota of APP/PS1 mice to levels resembling the wild-type control. Taken together, combination treatment outperformed NP106 or TML-6 monotherapy in ameliorating Aβ pathology and the nesting behavioral deficit in APP/PS1 mice. The superior effect might result from a more potent modulation of microglial function, cerebral inflammation, and the gut microbiota. This innovative treatment paradigm confers a new avenue to develop more efficacious AD treatments.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Antibodies, Monoclonal; Behavior, Animal; Biomarkers; Curcumin; Disease Management; Disease Models, Animal; Disease Susceptibility; Dose-Response Relationship, Drug; Drug Therapy, Combination; Immunohistochemistry; Mice; Mice, Knockout; Microbiota; Microglia; Molecular Targeted Therapy; Plaque, Amyloid; Presenilin-1

Alzheimer's disease (AD) is a progressive neurodegenerative disease that afflicts millions of people all over the world. Intracerebroventricular (ICV) injection of a sub-diabetogenic dose of streptozotocin (STZ) was established as an experimental animal model of AD. The present study was conducted to evaluate the efficacy of curcumin nanoparticles (CNs) against the behavioral, neurochemical and histopathological alterations induced by ICV-STZ. The animals were divided into: control animals, the animal model of AD that received a single bilateral ICV microinjection of STZ, and the animals protected by a daily oral administration of CNs for 6 days before the ICV-STZ injection. The animals of all groups were subjected to surgical operation on the 7th day of administration. Then the administration of distilled water or CNs was continued for 8 days. The ICV-STZ microinjection produced cognitive impairment as evident from the behavioral Morris water maze (MWM) test and induced oxidative stress in the cortex and hippocampus as indicated by the significant increases in lipid peroxidation and nitric oxide (NO) levels and the significant decrease in reduced glutathione (GSH) levels. It also produced a significant increase in acetylcholinesterase (AChE) and tumor necrosis-alpha (TNF-ɑ) and a significant decrease in Na+,K + -ATPase. In addition, a significant increase in amino acid neurotransmitters occurred in the hippocampus, whereas a significant decrease was obtained in the cortex of STZ-induced AD rats. CNs ameliorated the behavioral, immunohistochemical and most of the neurochemical alterations induced by STZ in the hippocampus and cortex. It may be concluded that CNs might be considered as a promising therapeutic agent for the treatment of AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Curcumin; Disease Models, Animal; Humans; Male; Maze Learning; Nanoparticles; Neurodegenerative Diseases; Oxidative Stress; Rats; Rats, Wistar; Streptozocin

J147 is a novel drug candidate developed to treat neurological dysfunction. Numerous studies have demonstrated the beneficial effects of J147 in cellular and animal models of disease which has led to the transitioning of the compound into human clinical trials. However, no biomarkers for its target engagement have been identified. Here, we determined if specific metabolites in the plasma could be indicative of J147's activity in vivo. Plasma lipidomics data from three independent rodent studies were assessed along with liver lipidomics data from one of the studies. J147 consistently reduced plasma free fatty acid (FFA) levels across the independent studies. Decreased FFA levels were also found in the livers of J147-treated mice that correlated well with those in the plasma. These changes in the liver were associated with activation of the AMP-activated protein kinase/acetyl-CoA carboxylase 1 signaling pathway. A reduction in FFA levels by J147 was confirmed in HepG2 cells, where activation of the AMPK/ACC1 pathway was seen along with increases in acetyl-CoA and ATP levels which correlated with enhanced cellular bioenergetics. Our data show that J147 targets liver cells to activate the AMPK/ACC1 signaling pathway and preserve energy at the expense of inhibiting FFA synthesis.

Topics: Acetyltransferases; Alzheimer Disease; AMP-Activated Protein Kinases; Animals; Curcumin; Fatty Acids, Nonesterified; Female; Hep G2 Cells; Humans; Lipid Metabolism; Liver; Male; Mice; Rats; Rats, Wistar; Signal Transduction

Curcumin derivatives B and N were developed as disaggregation agents of amyloid β (Aβ) fibrils. The detoxification provided by each compound at a concentration of 1 μM was observed in neuroblastoma cells. Furthermore, both compounds significantly rescued locomotion dysfunction in an Aβ-expressing

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Curcumin; Disease Models, Animal; Dose-Response Relationship, Drug; Drosophila; Molecular Structure

The inflammatory dysfunction of microglia from excess amyloid-β peptide (Aβ) disposal is an overlooked but pathogenic event in Alzheimer's disease (AD). Here, we exploit a native high-density lipoprotein (HDL)-inspired nanoscavenger (pHDL/Cur-siBACE1) that combines the trinity of phosphatidic acid-functionalized HDL (pHDL), curcumin (Cur), and β-site APP cleavage enzyme 1 targeted siRNA (siBACE1) to modulate microglial dysfunction. By mimicking the natural lipoprotein transport route, pHDL can penetrate the blood-brain barrier and sequentially target Aβ plaque, where Aβ catabolism is accelerated without microglial dysfunction. The benefit results are from a three-pronged modulation strategy, including promoted Aβ clearance with an antibody-like Aβ binding affinity, normalized microglial dysfunction by blocking the NF-κB pathway, and reduced Aβ production by gene silence (44%). After treatment, the memory deficit and neuroinflammation of APPswe/PSEN 1dE9 mice are reversed. Collectively, this study highlights the double-edged sword role of microglia and provides a promising tactic for modulating microglial dysfunction in AD treatment.

Topics: Alzheimer Disease; Animals; Curcumin; Disease Models, Animal; Lipoproteins, HDL; Mice; Mice, Transgenic; Microglia; Neuroinflammatory Diseases

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is not restricted to the neuronal compartment but includes important interactions with immune cells, including microglia. Protein aggregates, common pathological hallmarks of AD, bind to pattern recognition receptors on microglia and trigger an inflammatory response, which contributes to disease progression and severity. In this context, curcumin is emerging as a potential drug candidate able to affect multiple key pathways implicated in AD, including neuroinflammation. Therefore, we studied the effect of curcumin and its structurally related analogues

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Death; Curcumin; Humans; Microglia; Peptide Fragments

Alzheimer's disease (AD) is the most common neurodegenerative disorder without effective therapy and lack diagnosis strategy for preclinical AD patients. There is an urgent need for development of both early diagnosis and therapeutic intervention of AD.. Herein, we developed a nanotheranostics platform consisting of Curcumin (Cur), an anti-inflammatory molecule, and superparamagnetic iron oxide (SPIO) nanoparticles encapsulated by diblock 1,2-dio-leoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethylene glycol)] (DSPE-PEG) that are modified with CRT and QSH peptides on its surface. Furthermore, we demonstrated that this multifunctional nanomaterial efficiently reduced β-amyloid plaque burden specifically in APP/PS1 transgenic mice, with the process noninvasively detected by magnetic resonance imaging (MRI) and the two-dimensional MRI images were computed into three-dimension (3D) plot. Our data demonstrated highly sensitive in vivo detection of β-amyloid plaques which more closely revealed real deposition of Aβ than previously reported and we quantified the volumes of plaques for the first time based on 3D plot. In addition, memory deficits of the mice were significantly rescued, probably related to inhibition of NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasomes.. Gathered data demonstrated that this theranostic platform may have both early diagnostic and therapeutic potential in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognition; Curcumin; Disease Models, Animal; Magnetic Resonance Imaging; Mice; Mice, Transgenic; NLR Family, Pyrin Domain-Containing 3 Protein; Plaque, Amyloid; Theranostic Nanomedicine

Drug delivery systems that not only show efficacy through multiple therapeutic pathways but also facilitate patient drug use and exhibit a high bioavailability profile represent a promising strategy in the treatment of Alzheimer's disease (AD). Here, donepezil (DO)/memantine (MM)/curcumin (CUR)-loaded electrospun nanofibers (NFs) were produced for the treatment of AD. DSC, XRD, and FT-IR studies demonstrated the complete incorporation of the drug into PVA/PVP NFs. The disintegration profile was improved by loading the drugs in PVA/PVP with fast wetting (less than 1 s), the start of disintegration (21 s), and dispersion in 110 s. The desired properties for sublingual application were achieved with the dissolution of NFs in 240 s. The cell viability in DO/MM/CUR-loaded NFs was similar to the control group after 48 h in the cell culture. DO/MM/CUR-loaded NFs enhanced the expressions of BDNF (13.5-fold), TUBB3 (8.9-fold), Neurog2 (5.6-fold), NeuroD1 (5.8-fold), Nestin (166-fold), and GFAP (115-fold). DO/MM/CUR-loaded NFs and powder of these drugs contained in these fibers were daily administered sublingually to intracerebroventricular-streptozotocin (icv-STZ) treated rats. DO/MM/CUR-loaded NFs treatment improved the short-term memory damage and enhanced memory, learning ability, and spatial exploration talent. Results indicated that the levels of Aβ, Tau protein, APP, GSK-3β, AChE, and TNF-α were significantly decreased, and BDNF was increased by DO/MM/CUR-loaded NFs treatment compared to the AD group. In the histopathological analysis of the hippocampus and cortex, neuritic plaques and neurofibrillary nodes were not observed in the rats treated with DO/MM/CUR-loaded NFs. Taken together, the sublingual route delivery of DO/MM/CUR-loaded NFs supports potential clinical applications for AD.

Topics: Alzheimer Disease; Animals; Brain-Derived Neurotrophic Factor; Curcumin; Donepezil; Glycogen Synthase Kinase 3 beta; Memantine; Nanofibers; Rats; Spectroscopy, Fourier Transform Infrared

Alzheimer's disease (AD) is a fatal neurodegenerative disorder associated with severe dementia, progressive cognitive decline, and irreversible memory loss. Although its etiopathogenesis is still unclear, the aggregation of amyloid-β (Aβ) peptides into supramolecular structures and their accumulation in the central nervous system play a critical role in the onset and progression of the disease. On such a premise, the inhibition of the early stages of Aβ aggregation is a potential prevention strategy for the treatment of AD. Since several natural occurring compounds, as well as metal-based molecules, showed promising inhibitory activities toward Aβ aggregation, we herein characterized the interaction of an organoruthenium derivative of curcumin with Aβ(1-40) and Aβ(1-42) peptides, and we evaluated its ability to inhibit the oligomerization/fibrillogenesis processes by combining in silico and in vitro methods. In general, besides being less toxic to neuronal cells, the derivative preserved the amyloid binding ability of the parent compound in terms of equilibrium dissociation constants but (most notably) was more effective both in retarding the formation and limiting the size of amyloid aggregates by virtue of a higher hindering effect on the amyloid-amyloid elongation surface. Additionally, the complex protected neuronal cells from amyloid toxicity.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Curcumin; Humans; Ruthenium

Alzheimer's disease (AD) is a degenerative disorder characterized by the loss of synapses and neurons in the brain, and results in the accumulation of amyloid-based neurotic plaques. Amyloid-β oligomers (AβO) are widely accepted as the main neurotoxin that induces oxidative stress and neuronal loss in AD. In this study, an oxidative stress model of the neuroblastoma SH-SY5Y cell line exposed to AβO was established to simulate an AD cell model. Exposure to AβO significantly reduced the viability of cultured SH-SY5Y cells (p < 0.05) and significantly increased intracellular reactive oxygen species (ROS) (p < 0.01). AβO exposure also induced oxidative stress in SH-SY5Y cells. Furthermore, AβO significantly increased the level of hyperphosphorylation of tau at sites T181 and T205 in SH-SY5Y cells (p < 0.01). Using edaravone, a free radical scavenger with neuroprotective properties, as the control, the possible protective and anti-oxidative effects of curcumin (40 μM) and resveratrol (20 μM) were evaluated. The results suggest that curcumin and resveratrol decreased ROS generation, attenuated oxidative stress, inhibited tau hyperphosphorylation, and protected SH-SY5Y cells from AβO damage. Both curcumin and resveratrol are promising supplements or medicine as therapeutic agents for the treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Curcumin; Edaravone; Free Radical Scavengers; Humans; Neuroblastoma; Neuroprotective Agents; Neurotoxins; Oxidative Stress; Reactive Oxygen Species; Resveratrol

Alzheimer disease (AD) is a degenerative brain disease, which may lead to severe memory loss and other cognitive disorders. However, few effective drugs are available in the clinic at present. Curcumin, a major ingredient of traditional Chinese medicine, Curcuma Longa, has various pharmacological activities. Therefore, exploring clinical drugs based on the inhibition of AD pathological features is imperative.. First, we utilized the HERB database and Swisstarget Prediction database to get the related targets of curcumin and intersected with the AD targets. The intersection targets were used to construct the protein-protein interaction network and performed gene ontology and kyoto encyclopedia of genes and genomes analyses. Further, we obtained targets of curcumin against AD-related tau and aβ pathology via the AlzData database. These targets were applied to perform GEO and receiver operating characteristic analyses. Finally, the reliability of the core targets was evaluated using molecular docking technology.. We identified 49 targets of curcumin against AD, and kyoto encyclopedia of genes and genomes pathway enrichment analysis demonstrated that the Alzheimer disease pathway (has05010) was significantly enriched. Even more, we obtained 16 targets of curcumin-related Aβ and tau pathology. Among these targets, 8 targets involved the Alzheimer disease pathway and the biological process analyses showed that positive regulation of cytokine production (GO:0001819) was significantly enriched. Bioinformatic analyses indicated that HMOX1, CSF1R, NFKB1, GSK3B, BACE1, AR, or PTGS1 expression was significantly different compared to the control group in the AD patients. Finally, molecular docking studies suggested these genes have a good binding force with curcumin.. In this study, we identified curcumin exerted the effect of treating AD by regulating multitargets and multichannels through the method of network pharmacology.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Curcumin; Drugs, Chinese Herbal; Humans; Medicine, Chinese Traditional; Molecular Docking Simulation; Network Pharmacology; Reproducibility of Results; Signal Transduction

Alzheimer's disease (AD) is a neurodegenerative disease that leads to progressive cognitive decline. Several effective natural components have been identified for the treatment of AD. However, it is difficult to obtain conclusive evidence on the safety and effectiveness of natural components, because a variety of factors are associated with the progression of AD pathology. We hypothesized that a therapeutic effect could be achieved by combining multiple ingredients with different efficacies. The purpose of this study was thus to evaluate a combination treatment of curcumin (Cur) and ferulic acid (FA) for amyloid-β (Aβ)-induced neuronal cytotoxicity. The effect of Cur or FA on Aβ aggregation using thioflavin T assay was confirmed to be inhibited in a concentration-dependent manner by Cur single or Cur + FA combination treatment. The effects of Cur + FA on the cytotoxicity of human neuroblastoma (SH-SY5Y) cells induced by Aβ exposure were an increase in cell viability, a decrease in ROS and mitochondrial ROS, and repair of membrane damage. Combination treatment showed an overall higher protective effect than treatment with Cur or FA alone. These results suggest that the combined action mechanisms of Cur and FA may be effective in preventing and suppressing the progression of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Coumaric Acids; Curcumin; Humans; Neuroblastoma; Neurodegenerative Diseases; Neuroprotective Agents; Neurotoxicity Syndromes; Reactive Oxygen Species

Amyloid-β (Aβ) dimers are the smallest toxic species along the amyloid-aggregation pathway and among the most populated oligomeric accumulations present in the brain affected by Alzheimer's disease (AD). A proposed therapeutic strategy to avoid the aggregation of Aβ into higher-order structures is to develop molecules that inhibit the early stages of aggregation, i.e., dimerization. Under physiological conditions, the Aβ dimer is highly dynamic and does not attain a single well-defined structure but is rather characterized by an ensemble of conformations. In a recent study, a highly heterogeneous library of conformers of the Aβ dimer was generated by an efficient sampling method with constraints based on ion mobility mass spectrometry data. Here, we make use of the Aβ dimer library to study the interaction with two curcumin degradation products, ferulic aldehyde and vanillin, by molecular dynamics (MD) simulations. Ensemble docking and MD simulations are used to provide atomistic detail of the interactions between the curcumin degradation products and the Aβ dimer. The simulations show that the aromatic residues of Aβ, and in particular

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzaldehydes; Curcumin; Humans; Molecular Dynamics Simulation; Peptide Fragments

Topics: Alzheimer Disease; Brain; Curcumin; Drug Delivery Systems; Humans; Nanoparticles

To explore the potential mechanism of curcumin in the treatment of Alzheimer's disease (AD) and clarify the role of miR-146a in the neuroinflammatory response to AD.. Clinical case study: 20 AD patients and 20 age-gender matched non-inflammatory and non-dementia patients in the department of neurology of our hospital were included, peripheral venous blood and cerebrospinal fluid were collected, and mir-146a levels in peripheral blood and cerebrospinal fluid were detected by real-time fluorescence quantitative PCR. Animal experimental study group: There were 3 groups, including APP/PS1 mice control group, APP/PS1 mice low-dose curcumin treatment group, and C57BL/6J mice wild-type (WT) control group, with 10 mice in each group. mir-146a levels in mice brain tissue were detected by quantitative real-time PCR. Aβ, APP, complement factor H (CFH) and M1 microglia labeled IL-1 β and iNOS in temporal lobe tissues of mice were detected by using Westernblot method.. The plasma miRNA-146a level in AD group was 39.10±12.97 fmol/L, and that in control group was 60.54±13.16 fmol/L. The plasma miRNA-146a level in AD group was significantly lower than that in control group. The level of miRNA-146a in cerebrospinal fluid of AD group (25.16±5.16 fmol/L) was significantly higher than that of control group (11.35±3.58 fmol/L). After treatment with low dose curcumin, the level of miRNA-146a in APP/PS1 mice decreased significantly, and the expression of A β and APP/PS1 in temporal lobe of mice detected by Western blot decreased significantly, the levels of IL-1 β and iNOS protein decreased significantly, and the protein of CFH increased significantly.. miRNA-146a can be used as one of the potential biomarkers of AD. Low dose curcumin can significantly reduce the level of neuropro-inflammatory miR-146A, up-regulate the expression of CFH protein, inhibit the phenotype of M1 microglia, and play a role in the treatment of AD by promoting the phagocytosis and clearance mechanism of A β.

Topics: Alzheimer Disease; Animals; Curcumin; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; MicroRNAs; Temporal Lobe

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Curcumin; Humans; Multiple Sclerosis; Parkinson Disease

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Citrus; Curcuma; Disease Models, Animal; Mice; Peptide Fragments; Plant Extracts

In this study, four series of compounds with benzoxazolone and benzothiazolone cores were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease (AD). Additionally, in order to shed light on the effect of the carbonyl groups of benzoxazolone/benzothiazolone, benzoxazole/benzothiazole-containing analogues were also synthesized and evaluated. Inhibition potency of all final compounds towards cholinesterase enzymes and their antioxidant activity were tested. Subsequently, the anti-inflammatory activity, cytotoxicity, apoptosis, and Aβ aggregation inhibition tests were also performed for selected compounds. The results indicated that compounds 11c, a pentanamide derivative with benzothiazolone core, and 14b, a keton derivative with benzothiazolone core, were considered as promising multi-functional agents for further investigation against AD. The reversibility, kinetic and molecular docking studies were also performed for the compounds with the highest AChE 14b (eeAChE IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Benzoxazoles; Butyrylcholinesterase; Cell Proliferation; Cells, Cultured; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Horses; Humans; Mice; Molecular Structure; Neuroprotective Agents; Protein Aggregates; Structure-Activity Relationship; Thiazoles

To discover novel multifunctional agents for the treatment of Alzheimer's disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Benzofurans; Benzylidene Compounds; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Copper; Dose-Response Relationship, Drug; Electrophorus; Female; Humans; Male; Mannich Bases; Mice; Mice, Inbred Strains; Models, Molecular; Molecular Structure; Neuroprotective Agents; PC12 Cells; Peptide Fragments; Protein Aggregates; Rats; Structure-Activity Relationship

A novel series of dimethylamino chalcone-O-alkylamines derivatives was designed and synthesized as multifunctional agents for the treatment of AD. All the target compounds exhibited significant abilities to inhibit and disaggregate Aβ aggregation, and acted as potential selective AChE inhibitors, biometal chelators and selective MAO-B inhibitors. Among these compounds, compound TM-6 showed the greatest inhibitory activity against self-induced Aβ aggregation (IC50 = 0.88 μM) and well disaggregation ability toward self-induced Aβ aggregation (95.1%, 25 μM), the TEM images, molecular docking study and molecular dynamics simulations provided reasonable explanation for its high efficiency, and it was also found to be a remarkable antioxidant (ORAC-FL values of 2.1eq.), the best AChE inhibitor (IC50 = 0.13 μM) and MAO-B inhibitor (IC50 = 1.0 μM), as well as a good neuroprotectant. UV-visual spectrometry and ThT fluorescence assay revealed that compound TM-6 was not only a good biometal chelator by inhibiting Cu2+-induced Aβ aggregation (95.3%, 25 μM) but also could disassemble the well-structured Aβ fibrils (88.1%, 25 μM). Further, TM-6 could cross the blood-brain barrier (BBB) in vitro. More importantly, compound TM-6 did not show any acute toxicity in mice at doses of up to 1000 mg/kg and improved scopolamine-induced memory impairment. Taken together, these data indicated that TM-6, an excellent balanced multifunctional inhibitor, was a potential lead compound for the treatment of AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Amines; Amyloid beta-Peptides; Animals; Antioxidants; Binding Sites; Cell Survival; Chalcone; Drug Design; Humans; Kinetics; Metals; Molecular Docking Simulation; Monoamine Oxidase; Neuroprotective Agents; PC12 Cells; Protein Aggregates; Rats; Structure-Activity Relationship

A series of benzofuran piperidine derivatives were designed, synthesized and evaluated as multifunctional Aβ antiaggregant to treat Alzheimer's disease (AD). In vitro results revealed that all of them are very good Aβ antiaggregants and some of the compounds are potent acetylcholinesterase (AChE) inhibitors with moderate antioxidant property. Selected compounds were also tested for neuroprotection activity, LDH release, ATP production and inhibitory activity to prevent Aβ peptides binding to the cell membrane. The different modifications introduced in the structure of our lead compound 3 (hAChE IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Benzofurans; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Piperidines; Protein Aggregates; Protein Aggregation, Pathological; Structure-Activity Relationship

Topics: Alzheimer Disease; Amides; Amyloid; Coumaric Acids; Dose-Response Relationship, Drug; Humans; Molecular Structure; Protein Aggregates; Structure-Activity Relationship

Amyloid β (Aβ) aggregation inhibitor activity cliff involving a curcumin structure was predicted using the SAR Matrix method on the basis of 697 known Aβ inhibitors from ChEMBL (data set 2487). Among the compounds predicted, compound B was found to possess approximately 100 times higher inhibitory activity toward Aβ aggregation than curcumin. TEM images indicate that compound B induced the shortening of Aβ fibrils and increased the generation of Aβ oligomers in a concentration dependent manner. Furthermore, compound K, in which the methyl ester of compound B was replaced by the tert-butyl ester, possessed low cytotoxicity on N2A cells and attenuated Aβ-induced cytotoxicity, indicating that compound K would have an ability for preventing neurotoxicity caused by Aβ aggregation.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Butyrylcholinesterase; Cholinesterase Inhibitors; Curcumin; Dose-Response Relationship, Drug; Drug Development; Humans; Molecular Structure; Neuroprotective Agents; Protein Aggregates; Structure-Activity Relationship

A series of naringenin derivatives were designed and synthesized as multifunctional anti-Alzheimer's disease (AD) agents. The results showed that these derivatives displayed moderate-to-good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities at the micromolar range (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Carbamates; Chelating Agents; Cholinesterase Inhibitors; Drug Design; Electrophorus; Flavanones; Free Radical Scavengers; Horses; Kinetics; Molecular Docking Simulation; Molecular Structure; Peptide Fragments; Protein Binding; Protein Multimerization; Structure-Activity Relationship

Histone deacetylase 6 (HDAC6) is a potential target for Alzheimer's disease (AD). In this study, a series of novel phenothiazine-, memantine-, and 1,2,3,4-tetrahydro-γ-carboline-based HDAC6 inhibitors with a variety of linker moieties were designed and synthesized. As a hydrochloride salt, the phenothiazine-based hydroxamic acid W5 with a pyridyl-containing linker motif was identified as a high potent and selective HDAC6 inhibitor. It inhibited HDAC6 with an IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Survival; Copper; Dose-Response Relationship, Drug; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Molecular Structure; Neuroprotective Agents; Peptide Fragments; Structure-Activity Relationship; Tumor Cells, Cultured

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Curcumin; Fluorescent Dyes; Mice

The disorder of lipid metabolism, especially cholesterol metabolism, can promote Alzheimer's Disease. Curcumin can ameliorate lipid metabolic disorder in the brain of Alzheimer's Disease patients, while the mechanism is not clear. APP/PS1 (APPswe/PSEN1dE9) double transgenic mice were divided into dementia, low-dose, and high-dose groups and then fed for six months with different dietary concentrations of curcumin. Morris water maze was used to evaluate the transgenic mice's special cognitive and memory ability in each group. In contrast, the cholesterol oxidase-colorimetric method was used to measure total serum cholesterol and high-density lipoprotein levels. Immunohistochemistry was used to evaluate the expression of liver X receptor-β, ATP binding cassette A1 and apolipoprotein A1 of the hippocampus and Aβ42 in the brains of transgenic mice. The mRNA and protein expression levels of liver X receptor-β, retinoid X receptor-α and ATP binding cassette A1 were evaluated using qRT-PCR and Western blotting, respectively. Curcumin improved the special cognitive and memory ability of transgenic Alzheimer's Disease Mice. The total serum cholesterol decreased in Alzheimer's Disease mice fed the curcumin diet, while the high-density lipoprotein increased. The curcumin diet was associated with reduced expression of Aβ and increased expression of liver X receptor-β, ATP binding cassette A1, and apolipoprotein A1 in the CA1 region of the hippocampus. The mRNA and protein levels of retinoid X receptor-α, liver X receptor-β, and ATP binding cassette A1 were higher in the brains of Alzheimer's Disease mice fed the curcumin diet. Our results point to the mechanism by which curcumin improves lipid metabolic disorders in Alzheimer's Disease via the ATP binding cassette A1 transmembrane transport system.

Topics: Alzheimer Disease; Animals; ATP Binding Cassette Transporter 1; Curcumin; Disease Models, Animal; Dyslipidemias; Enzyme Inhibitors; Hippocampus; Lipid Metabolism; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic

A high dose of dexamethasone induces neurodegeneration by initiating the inflammatory processes that lead to neural apoptosis. A dexamethasone administration model induces overproduction of amyloid-β (Aβ) and tau protein hyperphosphorylation and shows abnormalities of cholinergic function similar to Alzheimer's disease (AD). This study aimed to investigate the protective effect of hexahydrocurcumin on the brain of dexamethasone-induced mice. The results showed that hexahydrocurcumin and donepezil attenuated the levels of amyloid precursor protein and β-secretase mRNA by reverse transcription polymerase chain reaction, decreased the expression of hyperphosphorylated tau, and improved synaptic function. Moreover, we found that hexahydrocurcumin treatment could decrease interleukin-6 levels by attenuating p65 of nuclear factor kappa-light-chain-enhancer (NF-κB) of activated beta cells. In addition, hexahydrocurcumin also decreased oxidative stress, as demonstrated by the expression of 4-hydroxynonenal and thereby prevented apoptosis. Therefore, our finding suggests that hexahydrocurcumin prevents dexamethasone-induced AD-like pathology and improves memory impairment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Curcumin; Dexamethasone; Disease Models, Animal; Male; Mice, Inbred ICR; Neuroprotective Agents

The most important hallmark in the neuropathology of Alzheimer's disease (AD) is the formation of amyloid-β (Aβ) fibrils due to the misfolding/aggregation of the Aβ peptide. Preventing or reverting the aggregation process has been an active area of research. Naturally occurring products are a potential source of molecules that may be able to inhibit Aβ42 peptide aggregation. Recently, we and others reported the anti-aggregating properties of curcumin and some of its derivatives in vitro, presenting an important therapeutic avenue by enhancing these properties.. To computationally assess the interaction between Aβ peptide and a set of curcumin derivatives previously explored in experimental assays.. The interactions of ten ligands with Aβ monomers were studied by combining molecular dynamics and molecular docking simulations. We present the in silico evaluation of the interaction between these derivatives and the Aβ42 peptide, both in the monomeric and fibril forms.. The results show that a single substitution in curcumin could significantly enhance the interaction between the derivatives and the Aβ42 monomers when compared to a double substitution. In addition, the molecular docking simulations showed that the interaction between the curcumin derivatives and the Aβ42 monomers occur in a region critical for peptide aggregation.. Results showed that a single substitution in curcumin improved the interaction of the ligands with the Aβ monomer more so than a double substitution. Our molecular docking studies thus provide important insights for further developing/validating novel curcumin-derived molecules with high therapeutic potential for AD.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Computer Simulation; Curcumin; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Protein Structure, Secondary

Curcumin and two bivalent compounds, namely 17MD and 21MO, both obtained by conjugation of curcumin with a steroid molecule that acts as a membrane anchor, were comparatively studied. When incorporated into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine the compounds showed a very limited solubility in the model membranes. Curcumin and the two bivalent compounds were also incorporated in membranes of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and quenching the fluorescence of pure curcumin or of the curcumin moiety in the bivalent compounds by acrylamide it was seen that curcumin was accessible to this water soluble quencher but the molecule was somehow located in a hydrophobic environment. This was confirmed by quenching with doxyl-phosphatidylcholines, indicating that the curcumin moieties of 17MD and 21MO were in a more polar environment than pure curcumin itself.

Topics: Alzheimer Disease; Curcumin; Humans; Hydrophobic and Hydrophilic Interactions; Lipid Bilayers; Magnetic Resonance Spectroscopy; Phosphatidylcholines; Water

The accumulation of β-amyloid (Aβ) aggregates in the brain occurs early in the progression of Alzheimer's disease (AD), and non-fibrillar soluble Aβ oligomers are particularly neurotoxic. During binding to Aβ fibrils, curcumin, which can exist in an equilibrium state between its keto and enol tautomers, exists predominantly in the enol form, and binding activity of the keto form to Aβ fibrils is much weaker. Here we described the strong binding activity the keto form of curcumin derivative Shiga-Y51 shows for Aβ oligomers and its scant affinity for Aβ fibrils. Furthermore, with imaging mass spectrometry we revealed the blood-brain barrier permeability of Shiga-Y51 and its accumulation in the cerebral cortex and the hippocampus, where Aβ oligomers were mainly localized, in a mouse model of AD. The keto form of curcumin derivatives like Shiga-Y51 could be promising seed compounds to develop imaging probes and therapeutic agents targeting Aβ oligomers in the brain.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Curcumin; Disease Models, Animal; Mice; Peptide Fragments

Geroprotectors are compounds that slow the biological aging process in model organisms and may therefore extend healthy lifespan in humans. It is hypothesized that they do so by preserving the more youthful function of multiple organ systems. However, this hypothesis has rarely been tested in any organisms besides

Topics: Aging; Alzheimer Disease; Animals; Brain; Caenorhabditis elegans; Curcumin; Disease Models, Animal; Drosophila melanogaster; Female; Kidney; Male; Mice; Protective Agents; Renal Insufficiency, Chronic

Synaptic failure is one of the principal events associated with cognitive dysfunction in Alzheimer's disease (AD). Preservation of existing synapses and prevention of synaptic loss are promising strategies to preserve cognitive function in AD patients. As a potent natural anti-oxidant, anti-amyloid, and anti-inflammatory polyphenol, curcumin (Cur) shows great promise as a therapy for AD. However, hydrophobicity of natural Cur limits its solubility, stability, bioavailability, and clinical utility for AD therapy. We have demonstrated that solid lipid curcumin particles (SLCP) have greater therapeutic potential than natural Cur in vitro and in vivo models of AD. In the present study, we have investigated whether SLCP has any preservative role on affected dendritic spines and synaptic markers in 5xFAD mice.. Six- and 12-month-old 5xFAD and age-matched wild-type mice received oral administration of SLCP (100 mg/kg body weight) or equivalent amounts of vehicle for 2 months. Neuronal morphology, neurodegeneration, and amyloid plaque load were investigated from prefrontal cortex (PFC), entorhinal cortex (EC), CA1, CA3, and the subicular complex (SC). In addition, the dendritic spine density from apical and basal branches was studied by Golgi-Cox stain. Further, synaptic markers, such as synaptophysin, PSD95, Shank, Homer, Drebrin, Kalirin-7, CREB, and phosphorylated CREB (pCREB) were studied using Western blots. Finally, cognitive and motor functions were assessed using open-field, novel object recognition (NOR) and Morris water maze (MWM) tasks after treatment with SLCP.. We observed an increased number of pyknotic and degenerated cells in all these brain areas in 5xFAD mice and SLCP treatment partially protected against those losses. Decrease in dendritic arborization and dendritic spine density from primary, secondary, and tertiary apical and basal branches were observed in PFC, EC, CA1, and CA3 in both 6- and 12-month-old 5xFAD mice, and SLCP treatments partially preserved the normal morphology of these dendritic spines. In addition, pre- and postsynaptic protein markers were also restored by SLCP treatment. Furthermore, SLCP treatment improved NOR and cognitive function in 5xFAD mice.. Overall, these findings indicate that use of SLCP exerts neuroprotective properties by decreasing amyloid plaque burden, preventing neuronal death, and preserving dendritic spine density and synaptic markers in the 5xFAD mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Animals; Curcumin; Dendritic Spines; Disease Models, Animal; Guanine Nucleotide Exchange Factors; Hippocampus; Humans; Lipids; Mice; Mice, Transgenic

Phosphodiesterase 4 (PDE4), mainly present in immune, epithelial, and brain cells, represents a family of key enzymes for the degradation of cyclic adenosine monophosphate (cAMP), which modulates inflammatory response. In recent years, the inhibition of PDE4 has been proven to be an effective therapeutic strategy for the treatment of neurological disorders. PDE4D constitutes a high-interest therapeutic target primarily for the treatment of Alzheimer's disease, as it is highly involved in neuroinflammation, learning ability, and memory dysfunctions. In the present study, a thorough computational investigation consisting of molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations based on the linear response approximation (LRA) method was performed to study dietary polyphenols as potential PDE4D inhibitors. The obtained results revealed that curcumin, 6-gingerol, capsaicin, and resveratrol represent potential PDE4D inhibitors; however, the predicted binding free energies of 6-gingerol, capsaicin, and resveratrol were less negative than in the case of curcumin, which exhibited the highest inhibitory potency in comparison with a positive control rolipram. Our results also revealed that the electrostatic component through hydrogen bonding represents the main driving force for the binding and inhibitory activity of curcumin, 6-gingerol, and resveratrol, while the van der Waals component through shape complementarity plays the most important role in capsaicin's inhibitory activity. All investigated compounds form hydrophobic interactions with residues Gln376 and Asn602 as well as hydrogen bonds with nearby residues Asp438, Met439, and Ser440. The binding mode of the studied natural compounds is consequently very similar; however, it significantly differs from the binding of known PDE4 inhibitors. The uncovered molecular inhibitory mechanisms of four investigated natural polyphenols, curcumin, 6-gingerol, capsaicin, and resveratrol, form the basis for the design of novel PDE4D inhibitors for the treatment of Alzheimer's disease with a potentially wider therapeutic window and fewer adverse side effects.

Topics: Alzheimer Disease; Capsaicin; Catechols; Curcumin; Cyclic Nucleotide Phosphodiesterases, Type 4; Fatty Alcohols; Humans; Molecular Dynamics Simulation; Polyphenols; Resveratrol

Amyloid-β (Aβ) peptides spontaneously aggregate into β- and cross-β-sheets in model brain membranes. These nanometer sized can fuse into larger micrometer sized clusters and become extracellular and serve as nuclei for further plaque and fibril growth. Curcumin and homotaurine represent two different types of Aβ aggregation inhibitors. While homotaurine is a peptic antiaggregant that binds to amyloid peptides, curcumin is a nonpeptic molecule that can inhibit aggregation by changing membrane properties. By using optical and fluorescent microscopy, X-ray diffraction, and UV-vis spectroscopy, we study the effect of curcumin and homotaurine on Aβ

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Brain; Curcumin; Humans; Peptide Fragments; Taurine

Alzheimer's disease (AD) is one of the greatest geriatric medicinal challenges of our century and is the main disease leading to dementia. Despite extensive scientific research advances, available disease-modifying treatment strategies remained limited; thus, increasing demand for new drugs. In recent years, medicinal plants attracted attention due to their potential role in dementia. In the present study, α and β anomers of curcumin glucosides (CGs) were synthesized and evaluated for Alzheimer's treatment. CGs were synthesized by fusion reaction as a novel and easy method with more advantages (high yield, short reaction time, and low chemicals), and the products were characterized using HNMR. Wistar male rats were used to administer different treatments. They divided into control, sham, Alzheimer, and test groups (Alzheimer + α anomer and Alzheimer + β anomer). Animals received normal saline, Scopolamine (1 mg/kg), high dose anomers, scopolamine, and two doses (12.5 and 25 mg/kg) of anomers, respectively, for 10 days. Then the Morris Water Maze (MWM) test was performed on all animals. Finally, the animals' brains were extracted and homogenized for glutathione, acetylcholine esterase activity, protein carbonyl, and lipid peroxide level detection. The escape latency and the distance towards the hidden platform in Morris water maze in the Alzheimer group were significantly higher than both the control and test groups. Besides, there were no significant differences between sham and control groups in all tests. Both anomers led to a significant increase in glutathione, and acetylcholine levels while they caused a decrease in lipid peroxidation and protein carbonyl levels in brain tissue. It seems that intranasal administration of both anomers positively influenced maze learning in scopolamine receiving subjects. Although both anomers resulted in similar biochemistry tests, a higher dose of β anomer indicated better results than α anomer not only in behavioral tests but also in biochemical tests.

Topics: Administration, Intranasal; Alzheimer Disease; Animals; Brain; Curcumin; Drug Combinations; Drug Delivery Systems; Glucosides; Male; Maze Learning; Rats; Rats, Wistar

The pathological aggregation of tau is one of the major contributing factors for several neurodegenerative tauopathies, including Alzheimer's disease. Here, we report that C1, a synthetic derivative of curcumin, strongly inhibited both the aggregation and filament formation of purified tau and protected neuroblastoma cells from the deleterious effects of the tau oligomers. Using confocal microscopy, C1 was found to reduce both the size and number of the tau droplets and increased the critical concentration of tau required for the droplet formation

Topics: Alzheimer Disease; Curcumin; Humans; Neuroblastoma; tau Proteins; Tauopathies

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia. Despite research efforts, currently there are no effective pharmacotherapeutic options for the prevention and treatment of AD. Recently, numerous studies highlighted the beneficial effects of curcumin (CUR), a natural polyphenol, in the neuroprotection. Especially, its dual antioxidant and anti-inflammatory properties attracted the interest of researchers. In fact, besides its antioxidant and anti-inflammatory properties, this biomolecule is not degraded in the intestinal tract. Additionally, CUR is able to cross the blood-brain barrier and could therefore to be used to treat neurodegenerative pathologies associated with oxidative stress, inflammation and apoptosis. The present study aimed to assess the ability of CUR to induce neuronal protective and/or recovery effects on a rat model of neurotoxicity induced by aluminum chloride (AlCl

Topics: Acetylcholinesterase; Aluminum Chloride; Alzheimer Disease; Animals; Anxiety; Apoptosis; Body Weight; Cell Survival; Cognitive Dysfunction; Curcumin; Cytokines; Disease Models, Animal; Hippocampus; Inflammation; Inflammation Mediators; Male; Nerve Degeneration; Neuroprotective Agents; Neurotoxicity Syndromes; Organ Size; Oxidative Stress; Rats, Wistar

Exosomes are cell-derived vesicles that act as carriers for proteins and nucleic acids, with therapeutic potential and high biocompatibility. We propose a new concept of exosome-like liposomes for controlled delivery. The goal of this work was to develop a new type of liposomes with a unique mixture of phospholipids, similar to naturally occurring exosomes but overcoming their limitations of heterogeneity and low productivity, for therapeutic delivery of bioactive compounds. Curcumin was chosen as model compound, as it is a phytochemical molecule known to have antioxidant and anti-inflammatory properties, which can protect the brain against oxidative stress and reduce β-amyloid accumulation, major hallmarks of Alzheimer's disease (AD). These new liposomes can efficiently encapsulate hydrophobic curcumin, yielding particles with a size smaller than 200 nm, and a polydispersity index lower than 0.20, which make them ideal for crossing the blood-brain barrier. These particles have a long shelf life, being stable up to 6 months. The curcumin encapsulation efficiency was higher than 85% (up to approximately 94%). Curcumin-loaded liposomes were not cytotoxic (up to 20 μM curcumin, and 200 μM of exo-liposomes), and significantly reduced oxidative stress induced in SH-SY5Y neuronal cells, indicating their potential for neuroprotection. They also do not show any toxicity and are internalized in zebrafish embryos, concentrating in lipid enriched areas, as the brain and the yolk sac. Such innovative carriers are a new effective approach to deliver drugs into the brain, as these are stable, protect the cargo and are uptaken by neuronal cells. Upon internalization, liposomes release the therapeutic biomolecules, resulting in successful neuroprotection, being a positive alternative strategy for AD therapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Curcumin; Exosomes; Liposomes; Zebrafish

1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (tetrahydrocurcumin, THC) is a major bioactive metabolite of curcumin, demonstrating the potential anti-inflammatory, antioxidant and neuroprotective properties, etc. In this study, it was found that Aβ induced decreased cell viability, cell cycle arrest and apoptosis in BV-2 cells, which were ameliorated by THC. In vivo, THC administration rescued learning and memory, and reduced Aβ burden in the hippocampus of APP/PS1 mice. By proteomic analysis of the hippocampus of mice, 157 differentially expressed proteins were identified in APP/PS1 mice treated with THC (comparing with APP/PS1 mice), which also suggested that the effects of THC on the cell cycle and apoptosis were mostly related to the "Ras signaling pathway", etc. In APP/PS1 mice, the down-regulation of Gab2 and K-Ras, and the up-regulation of caspase-3, TGF-β1 and TNF-ɑ were observed; THC attenuated the abnormal expression of Gab2, K-Ras, caspase-3 and TNF-ɑ, and up-regulated TGF-β1 and Bag1 expression. In BV-2 cells, Aβ induced the down-regulation of Gab2, K-Ras and TGF-β1, and the overexpression of caspase-3, PARP1, cleaved-PARP1 and TNF-ɑ, which were restored by THC. Moreover, THC up-regulated Bag1 expression in Aβ-treated BV-2 cells. The decreased transcriptional expression of Ccnd2 and Cdkn1a were also observed in Aβ-treated BV-2 cells, and THC alleviated the down-regulation of Ccnd2. For the first time, we identified that the action of THC in preventing AD was associated with inhibition of cell cycle arrest and apoptosis of microglia via the Ras/ERK signaling pathway, shedding new light on the role of THC in alleviating the progression of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apoptosis; Cell Cycle Checkpoints; Cell Line; Curcumin; Cyclin D2; Disease Models, Animal; Down-Regulation; Hippocampus; Humans; MAP Kinase Signaling System; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Proteomics; ras Proteins; Signal Transduction; Up-Regulation

The abnormal self-assembly of amyloid-beta (Aβ) peptides into oligomers, as well as insoluble fibrils, has been identified as a key factor for monitoring the progression of Alzheimer's disease (AD). The noninvasive imaging of Aβ aggregates utilizing chemical probes can be a powerful and practical technique for accurately diagnosing and monitoring the progress of AD, as well as evaluating the effectiveness of therapeutic drug candidates in treating or managing it. Particularly, the near-infrared (NIR) fluorescence imaging of Aβ plaques is a potentially promising approach toward the efficient detection of the biomarker. In this study, we describe a new NIR fluorophore, which was based on curcumin derivatives. The fluorophore is equipped with desirable optical properties for in vivo brain imaging. The emission wavelength of the probe, 8b, is 667 nm, and its fluorescent intensity is significantly increased through binding with the Aβ aggregates. The probe allows the clear visualization of the Aβ plaques 10 min post administration, and the intensity of the fluorescent signal in the brain of a 5XFAD transgenic mouse model is more than three times higher than that of the normal control group. These results demonstrate that the designed probe can be an effective tool for visualizing Aβ plaques, as well as investigating the pathological progress of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Binding Sites; Brain; Curcumin; Female; Fluorescent Dyes; Humans; Mice; Mice, Transgenic; Molecular Docking Simulation; Optical Imaging; Protein Aggregates; Spectroscopy, Near-Infrared

Amyloid-β (Aβ) deposition in the brain has been implicated in the development of Alzheimer's disease (AD), and neuroinflammation generates AD progression. Therapeutic effects of anti-inflammatory approaches in AD are still under investigation. Curcumin, a potent anti-inflammatory and antioxidant, has demonstrated therapeutic potential in AD models. However, curcumin's anti-inflammatory molecular mechanisms and its associated cognitive impairment mechanisms in AD remain unclear. The high-mobility group box-1 protein (HMGB1) participates in the regulation of neuroinflammation. Herein, we attempted to evaluate the anti-inflammatory effects of chronic oral administration of curcumin and HMGB1 expression in APP/PS1 transgenic mice AD model. We found that transgenic mice treated with a curcumin diet had shorter escape latencies and showed a significant increase in percent alternation, when compared with transgenic mice, in the Morris water maze and Y-maze tests. Additionally, curcumin treatment could effectively decrease HMGB1 protein expression, advanced glycosylation end product-specific receptor (RAGE), Toll-like receptors-4 (TLR4) and nuclear factor kappa B (NF-κB) in transgenic mice hippocampus. However, amyloid plaques detected with thioflavin-S staining in transgenic mice hippocampus were not affected by curcumin treatment. In contrast, curcumin significantly decreased GFAP-positive cells, as assessed by immunofluorescence staining. Taken together, these data indicate that oral administration of curcumin may be a promising agent to attenuate memory deterioration in AD mice, probably inhibiting the HMGB1-RAGE/TLR4-NF-κB inflammatory signalling pathway.

Topics: Alzheimer Disease; Animals; Curcumin; Hippocampus; HMGB1 Protein; Male; Mice; Mice, Transgenic; Receptor for Advanced Glycation End Products

A novel series of graveolinine derivatives were synthesized and evaluated as potential anti-Alzheimer agents. Compound 5f exhibited the best inhibitory activity for acetylcholinesterase (AChE) and had surprisingly potent inhibitory activity for butyrylcholinesterase (BuChE), with IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Butyrylcholinesterase; Cell Survival; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Electrophorus; Hep G2 Cells; Horses; Humans; Male; Methoxsalen; Mice; Molecular Structure; PC12 Cells; Peptide Fragments; Rats; Structure-Activity Relationship

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apigenin; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Ligands; Microsomes, Liver; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; Rats; Rivastigmine; Structure-Activity Relationship; Zebrafish

A series of novel flurbiprofen-clioquinol hybrids were designed and synthesized as multifunctional agents for Alzheimer's disease therapy, and their potential was evaluated through various biological experiments. In vitro studies showed that most target compounds exhibited significant ability to inhibit self- and Cu

Topics: Alzheimer Disease; Amyloid beta-Peptides; Clioquinol; Drug Discovery; Flurbiprofen; Humans; Ligands; Membranes, Artificial; Models, Molecular; Molecular Structure; Protein Conformation; Structure-Activity Relationship

Topics: Acetylcholinesterase; Aluminum Chloride; Alzheimer Disease; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Development; Humans; Ligands; Molecular Structure; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Structure-Activity Relationship; Zebrafish

A series of phthalide alkyl tertiary amine derivatives were designed, synthesized and evaluated as potential multi-target agents against Alzheimer's disease (AD). The results indicated that almost all the compounds displayed significant AChE inhibitory and selective activities. Besides, most of the derivatives exhibited increased self-induced Aβ

Topics: Acetylcholinesterase; Alzheimer Disease; Amines; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Drug Design; Female; Male; Membranes, Artificial; Mice; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Permeability; Protein Aggregation, Pathological; Random Allocation; Rats

A novel series of O-carbamoyl ferulamide derivatives were designed by multitarget-directed ligands (MTDLs) strategy, the derivatives were synthesized and evaluated to treat Alzheimer's disease (AD). In vitro biological evaluation demonstrated that compound 4f was the best pseudo-irreversible hBChE (human butyrylcholinesterase) inhibitor with an IC

Topics: Alzheimer Disease; Amides; Amyloid beta-Peptides; Animals; Cell Line; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Humans; Ligands; Mice; Mice, Inbred Strains; Microsomes, Liver; Molecular Structure; Peptide Fragments; Positron Emission Tomography Computed Tomography; Protein Aggregates; Rats; Structure-Activity Relationship; Zebrafish

A series of rasagiline-clorgyline hybrids was designed, synthesized and investigated in vitro for their inhibition of monoamine oxidase and amyloid-β aggregation. Most of compounds were found to be selective and highly potent hMAO-B inhibitors showing IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line, Tumor; Cell Survival; Clorgyline; Dose-Response Relationship, Drug; Drug Design; Humans; Indans; Male; Models, Molecular; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Peptide Fragments; Protein Aggregates; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

A novel series of triazole tethered coumarin-benzotriazole hybrids based on donepezil skeleton has been designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD). Among the synthesized compounds 13b showed most potent acetylcholinesterase (AChE) inhibition (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Cholinesterase Inhibitors; Coumarins; Dose-Response Relationship, Drug; Humans; Molecular Structure; Peptide Fragments; Protein Aggregates; Protein Aggregation, Pathological; Structure-Activity Relationship; Triazoles

A novel series of deoxyvasicinone-tetrahydro-beta-carboline hybrids were synthesized and evaluated as acetylcholinesterase (AChE) and β-amyloid peptide (Aβ) aggregation inhibitors for the treatment of Alzheimer's disease. The results revealed that the derivatives had multifunctional profiles, including AChE inhibition, Aβ

Topics: Acetylcholinesterase; Alkaloids; Alzheimer Disease; Amyloid beta-Peptides; Carbolines; Cell Line; Cholinesterase Inhibitors; Humans; Molecular Docking Simulation; Peptide Fragments; Protein Aggregates; Protein Aggregation, Pathological

Alzheimer's disease (AD) is the leading cause of dementia, which characterized by toxic senile plaques is composed of amyloid-β (Aβ). β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is the rate-limiting protease in Aβ generation. Therefore, pharmacology BACE1 inhibition is one of the prime targets for potential treatment of AD. Curcumin, a yellow polyphenol derived from the rhizomes of the plant Curcuma longa Linn, has been reported to cross the blood-brain barrier and prevent Aβ aggregation in AD models. However, its neuroprotective mechanism is still unclear. In the present study, we find that curcumin markedly reduces Aβ levels in HEK293-APPswe cells. Our results show that curcumin inhibits BACE1 gene expression in SH-SY5Y cells at transcriptional and translational levels. Furthermore, we reveal that nuclear factor kappa B (NFκB) signaling is involved in the regulation of curcumin on BACE1. Interestingly, the estrogenicity of curcumin is found to partially contribute to its protective action. Our data show that curcumin activates estrogen receptor β (ERβ) selectively and the activation of ERβ directly effects on the upstream factors of the NFκB signaling pathway. The above results indicate that curcumin reduces BACE1 expression through ERβ and NFκB pathway, providing a novel mechanism for curcumin as a candidate for AD therapy.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Cell Line, Tumor; Curcumin; Estrogen Receptor beta; HEK293 Cells; Humans; NF-kappa B; Signal Transduction

Accumulating studies have suggested that targeting transcription factor EB (TFEB), an essential regulator of autophagy-lysosomal pathway (ALP), is promising for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). However, potent and specific small molecule TFEB activators are not available at present. Previously, we identified a novel TFEB activator named curcumin analog C1 which directly binds to and activates TFEB. In this study, we systematically investigated the efficacy of curcumin analog C1 in three AD animal models that represent beta-amyloid precursor protein (APP) pathology (5xFAD mice), tauopathy (P301S mice) and the APP/Tau combined pathology (3xTg-AD mice). We found that C1 efficiently activated TFEB, enhanced autophagy and lysosomal activity, and reduced APP, APP C-terminal fragments (CTF-β/α), β-amyloid peptides and Tau aggregates in these models accompanied by improved synaptic and cognitive function. Knockdown of TFEB and inhibition of lysosomal activity significantly inhibited the effects of C1 on APP and Tau degradation in vitro. In summary, curcumin analog C1 is a potent TFEB activator with promise for the prevention or treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Line, Tumor; Chromosome Pairing; Cognitive Dysfunction; Curcumin; Disease Models, Animal; Glycogen Synthase Kinase 3 beta; Lysosomes; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Neurons; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; tau Proteins

Alzheimer's disease (AD) is an irreversible neurodegenerative disease. Recent identification of AD biomarkers has led to the diagnosis of AD before the onset of dementia. It has been shown that Drosophila melanogaster is a valuable model for studying human neurodegeneration, including AD. According to its properties, curcumin shows promising potential for the diagnosis of AD. In order to improve its use, new formulations, including nanotechnology-based delivery systems, have been applied. The current study aims to diagnose AD by detecting the accumulation of amyloid beta-peptide via carbon-dot-curcumin nanoparticle conjugation in Drosophila. The accumulation of amyloid beta-peptide has been detected via the conjugate using the fluorescence imaging technique. These results suggest that carbon-dot-curcumin nanoparticle conjugation could be used as a diagnostic tool for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Biomarkers; Carbon; Curcumin; Disease Models, Animal; Drosophila melanogaster; Early Diagnosis; Humans; Microscopy, Electron, Transmission; Models, Molecular; Protein Conformation; Quantum Dots

CRANAD-28, a difluoroboron curcumin analogue, has been demonstrated in earlier reports to successfully label amyloid beta (Aβ) plaques for imaging both ex vivo and in vivo. CRANAD-28's imaging brightness, ability to penetrate the blood brain barrier, and low toxicity make the compound a potentially potent imaging tool in Alzheimer's research. In this study, the Aβ-labeling ability of CRANAD-28 was investigated in further detail using histological staining to assess different criteria, including stained Aβ plaque brightness, Aβ plaque size, and Aβ plaque number count. The results of this study demonstrated CRANAD-28 to be superior across all criteria assessed. Furthermore, CRANAD-28 and IBA-1 antibody were used to label Aβ-plaques and microglia respectively. Statistical analysis with Spearman regression revealed a statistically significant negative correlation between the size of labeled Aβ plaques and surrounding microglia density. This finding provides interesting insight into Aβ plaque and microglia dynamism in AD pathology and corroborates the findings of previous studies. In addition, we found that CRANAD-28 provided distinct spectral signatures for Aβs in the core and periphery of the plaques. Based on the study's results, CRANAD-28 could be considered as an alternative standard for imaging Aβ-plaques in future research studies.

Topics: Alzheimer Disease; Animals; Benzothiazoles; Boron Compounds; Brain; Curcumin; Disease Models, Animal; Female; Fluorescent Dyes; Humans; Mice; Mice, Transgenic; Microglia; Microscopy, Confocal; Microtomy; Plaque, Amyloid; Staining and Labeling

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and no effective therapies have been found to prevent or cure AD to date. Berberine and curcumin are extracts from traditional Chinese herbs that have a long history of clinical benefits for AD. Here, using a transgenic AD mouse model, we found that the combined berberine and curcumin treatment had a much better effect on improving the cognitive function of mice than the single-drug treatment, suggesting synergic effects of the combined berberine and curcumin treatment. In addition, we found that the combined berberine and curcumin treatment had significant synergic effects on reducing soluble amyloid-β-peptide

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspartic Acid Endopeptidases; Berberine; Brain; Cognition; Curcumin; Drug Synergism; Female; Male; Mice; Mice, Transgenic; Oxidative Stress; Peptide Fragments

Alzheimer's disease (AD) is a neurodegenerative disease with increasing prevalence worldwide, while there are no effective drugs at present. Curcumin, a natural polyphenolic substance isolated from turmeric, is a promising natural compound to combat AD, but its pharmacology remains to be fully understood for its poor in vivo bioavalibility. Inspired by the recently reported associations between gut microbiota and AD development, the present study investigated the interactions of curcumin with gut microbiota of APP/PS1 double transgenic mice from two directions: (i) curcumin influences gut microbiota, and (ii) gut microbiota biotransform curcumin. It was found that curcumin administration tended to improve the spatial learning and memory abilities and reduce the amyloid plaque burden in the hippocampus of APP/PS1 mice. On the one hand, curcumin administration altered significantly the relative abundances of bacterial taxa such as Bacteroidaceae, Prevotellaceae, Lactobacillaceae, and Rikenellaceae at family level, and Prevotella, Bacteroides, and Parabacteroides at genus level, several of which have been reported to be key bacterial species associated with AD development. On the other hand, a total of 8 metabolites of curcumin biotransformed by gut microbiota of AD mice through reduction, demethoxylation, demethylation and hydroxylation were identified by HPLC-Q-TOF/MS, and many of these metabolites have been reported to exhibit neuroprotective ability. The findings provided useful clues to understand the pharmacology of curcumin and microbiome-targeting therapies for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Bacteria; Biotransformation; Curcumin; Disease Models, Animal; Gastrointestinal Microbiome; Male; Memory; Mice; Mice, Transgenic; Plaque, Amyloid

Curcumin, a molecule of labile natural product, has multiplex pharmacological effects, including antioxidant, antimicrobial, and anticancer effects as well as anti-Alzheimer's disease (AD) properties. However, the drawbacks of curcumin such as poor stability and bioavailability seriously limited its application in drug development. Numerous literature studies suggested the conversion of curcumin to metal complexes and explored the clearance of β-amyloid fibrils by curcumin conjugates. However, the research about the inhibition effect of curcumin complex on τ protein aggregation is progressing slowly, and its interactive orientation with the related proteins from the steric effect has been ignored. Inspired by the perspective on interactive orientation, we conjugated curcumin molecule on the positive-charged scaffold of Ru(II) complexes (bipyridine for Ru1, phenanthroline for Ru2) to construct an octahedral structure. After being conjugated with a ruthenium octahedral framework, curcumin exhibited a stronger ability to not only inhibit aggregation of R3, the τ peptide corresponding to the third repeat unit of the microtubule binding domain (residues 306-336 in full τ) (Ru1 with an IC

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Curcumin; Humans; Ruthenium; tau Proteins

Biomimetic nanotechnology represents a promising approach for the delivery of therapeutic agents for the treatment of complex diseases. Recently, neuronal mitochondria have been proposed to serve as a promising therapeutic target for sporadic Alzheimer's disease (AD). However, the efficient intravenous delivery of therapeutic agents to neuronal mitochondria in the brain remains a major challenge due to the complicated physiological and pathological environment. Herein, we devised and tested a strategy for functional antioxidant delivery to neuronal mitochondria by loading antioxidants into red blood cell (RBC) membrane-camouflaged human serum albumin nanoparticles bearing T807 and triphenylphosphine (TPP) molecules attached to the RBC membrane surface (T807/TPP-RBC-NPs). With the advantage of the suitable physicochemical properties of the nanoparticles and the unique biological functions of the RBC membrane, the T807/TPP-RBC-NPs are stabilized and promote sustained drug release, providing improved biocompatibility and long-term circulation. Under the synergistic effects of T807 and TPP, T807/TPP-RBC-NPs can not only penetrate the blood-brain barrier (BBB) but also target nerve cells and further localize in the mitochondria. After encapsulating curcumin (CUR) as the model antioxidant, the research data demonstrated that CUR-loaded T807/TPP-RBC-NPs can relieve AD symptoms by mitigating mitochondrial oxidative stress and suppressing neuronal death both in vitro and in vivo. In conclusion, the intravenous neuronal mitochondria-targeted biomimetic engineered delivery nanosystems provides an effective drug delivery platform for brain diseases. STATEMENT OF SIGNIFICANCE: The efficient intravenous delivery of therapeutic agents to neuronal mitochondria in the brain remains a major challenge for drug delivery due to the complicated physiological and pathological environment. To address this need, various types of nanovessels have been fabricated using a variety of materials in the last few decades. However, problems with the synthetic materials still exist and even cause toxicology issues. New findings in nanomedicine are promoting the development of biomaterials. Herein, we designed a red blood cell (RBC) membrane-coated human serum albumin nanoparticle dual-modified with T807 and TPP (T807/TPP-RBC-NPs) to accomplish these objectives. After encapsulating curcumin as the model drug, the research data demonstrated that the intravenous neuronal mitochondria-targeted

Topics: Alzheimer Disease; Animals; Biomimetics; Curcumin; Mice; Mitochondria; Nanoparticles; Neurons

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world, and there is currently no potent medicine for the treatment of ADs. Curcumin, a primary chemical contained in the ancient Indian herb known as turmeric, has been extensively studied and shown to be effective in inhibiting the aggregations of amyloid-β and tau proteins, both of which are observed in the brains of AD patients. In the present study, we focused on the tau protein and investigated its specific interactions with curcumin derivatives, using molecular simulations based on molecular docking, molecular mechanics and ab initio fragment molecular orbital calculations. Based on the results, we attempted to propose novel potent inhibitors against the tau protein aggregation. Our molecular simulations provide useful information for developing novel medicines for the treatment of ADs.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Curcumin; Humans; Molecular Docking Simulation; Space Simulation; tau Proteins

Although many therapeutic strategies for Alzheimer's disease (AD) have been explored, these strategies are seldom used in the clinic. Therefore, AD therapeutic research is still urgently needed. One major challenge in the field of nanotherapeutics is to increase the selective delivery of drugs to a targeted location. Herein, we devised and tested a strategy for delivery of nanoparticles to neurons to inhibit tau aggregation by directly targeting p-tau.. Curcumin (CUR) is loaded onto red blood cell (RBC) membrane-coated PLGA particles bearing T807 molecules attached to the RBC membrane surface (T807/RPCNP). With the advantage of the suitable physicochemical properties of the PLGA nanoparticles and the unique biological functions of the RBC membrane, the RPCNP are stabilized and promote sustained CUR release, which provided improved biocompatibility and resulted in long-term presence in the circulation. Under the synergistic effects of T807, T807/RPCNP can not only effectively penetrate the blood-brain barrier (BBB), but they also possess high binding affinity to hyperphosphorylated tau in nerve cells where they inhibit multiple key pathways in tau-associated AD pathogenesis. When CUR was encapsulated, our data also demonstrated that CUR-loaded T807/RPCNP NPs can relieve AD symptoms by reducing p-tau levels and suppressing neuronal-like cells death both in vitro and in vivo. The memory impairment observed in an AD mouse model is significantly improved following systemic administration of CUR-loaded T807/RPCNP NPs.. Intravenous neuronal tau-targeted T807-modified novel biomimetic nanosystems are a promising clinical candidate for the treatment of AD.

Topics: Alzheimer Disease; Animals; Apoptosis; Biomimetic Materials; Blood-Brain Barrier; Cell Line; Curcumin; Disease Models, Animal; Drug Carriers; Hippocampus; Humans; Maze Learning; Mice; Nanoparticles; Neurons; Protective Agents; tau Proteins

Curcumin, a major component of Indian saffron through clinical studies, revealed its neuroprotective effect in neurodegenerative diseases. However, it has not been utilized alone orally due to its low bioavailability. There are certain strategies to overcome the drawbacks such as poor absorption and low aqueous solubility. Many strategies are utilized to increase the systemic availability of curcumin. Among them, the steady intestinal and liver metabolism of curcumin by a curcumin adjuvant (enzyme inhibitor/inducer) is an important and less engrossed strategy for improving the overall systemic bioavailability of curcumin. Here, we assess the effect of probiotic Lactobacillus rhamnosus as a curcumin adjuvant (potentiate the effect of curcumin) in scopolamine-induced dementia in mice. To induce amnesia, scopolamine was used in a mouse model (1 mg/kg, daily for 10 days i.p.). After execution of behavioural tests (Morris water maze test), brains and liver were isolated for further neurochemical and histopathology examination. Our results showed a significant increase in antioxidant enzyme levels in curcumin with a probiotic group compared with curcumin alone. Besides, histopathology study results showed less neuronal damage of curcumin with probiotics as compared with the curcumin and scopolamine alone groups. Additionally, curcumin with probiotics improved memory and cognitive functions in the behavioural study with the significance of p ≤ 0.0001. In conclusion, curcumin with probiotics has greater activity as compared with curcumin alone and reverses the hallmarks of Alzheimer's disease (AD).

Topics: Alzheimer Disease; Animals; Cholinergic Antagonists; Curcumin; Drug Synergism; Female; Lacticaseibacillus rhamnosus; Maze Learning; Memory Disorders; Mice; Neuroprotective Agents; Probiotics; Scopolamine

Alzheimer's disease (AD) is the most common form of dementia with the numbers expected to increase dramatically as our society ages. There are no treatments to cure, prevent, or slow down the progression of the disease. Age is the single greatest risk factor for AD. However, to date, AD drug discovery efforts have generally not taken this fact into consideration. Multiple changes associated with brain aging, including neuroinflammation and oxidative stress, are important contributors to disease development and progression. Thus, due to the multifactorial nature of AD, the one target strategy to fight the disease needs to be replaced by a more general approach using pleiotropic compounds to deal with the complexity of the disease. In this perspectives piece, our alternative approach to AD drug development based on the biology of aging is described. Starting with plants or plant-derived natural products, we have used a battery of cell-based screening assays that reflect multiple, age-associated toxicity pathways to identify compounds that can target the aspects of aging that contribute to AD pathology. We have found that this combination of assays provides a replicable, cost- and time-effective screening approach that has to date yielded one compound in clinical trials for AD (NCT03838185) and several others that show significant promise.

Topics: Aging; Alzheimer Disease; Antioxidants; Curcumin; Eriodictyon; Ethnopharmacology; Flavonols; Humans; Indole Alkaloids; Neuroprotective Agents; Plant Preparations

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Cells, Cultured; Cholinesterase Inhibitors; Curcumin; Humans; Neurons; Neuroprotective Agents; Pharmacokinetics; Reactive Oxygen Species; Resveratrol; Triazoles

Galantamine (GAL) and curcumin (CU) are alkaloids used to improve symptomatically neurodegenerative conditions like Alzheimer's disease (AD). GAL acts mainly as an inhibitor of the enzyme acetylcholinesterase (AChE). CU binds to amyloid-beta (Aβ) oligomers and inhibits the formation of Aβ plaques. Here, we combine GAL core with CU fragments and design a combinatorial library of GAL-CU hybrids as dual-site binding AChE inhibitors. The designed hybrids are screened for optimal ADME properties and BBB permeability and docked on AChE. The 14 best performing compounds are synthesized and tested in vitro for neurotoxicity and anti-AChE activity. Five of them are less toxic than GAL and CU and show activities between 41 and 186 times higher than GAL.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Binding Sites; Blood-Brain Barrier; Cell Line; Cholinesterase Inhibitors; Combinatorial Chemistry Techniques; Curcumin; Galantamine; Humans; Mice; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship

Drugs for the treatment of Alzheimer's disease (AD) are in urgent demand due to the unmet need and the social burden associated with the disease. Curcumin has been historically considered as a beneficial product for anti-aging and AD. However, many efforts to develop curcumin for clinical use are hindered mainly due to its poor bioavailability. Recent development in drug delivery and structural design has resolved these issues. In this study, we identified a small molecule, TML-6, as a potential drug candidate for AD through screening a panel of curcumin derivatives using six biomarker platforms related to aging biology and AD pathogenesis. The structural modification of TML-6 is designed to improve the stability and metabolism of curcumin. Cell biological studies demonstrated that TML-6 could inhibit the synthesis of the β-amyloid precursor protein and β-amyloid (Aβ), upregulate Apo E, suppress NF-κB and mTOR, and increase the activity of the anti-oxidative

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Behavior, Animal; Brain; Curcumin; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Mice; Microglia; Neuroprotective Agents; NF-E2-Related Factor 2; Plaque, Amyloid

In this study, we compared the effects of two well-known natural compounds on the early step of the fibrillation process of amyloid-β (1-40), responsible for the formation of plaques in the brains of patients affected by Alzheimer's disease (AD). The use of extensive replica exchange simulations up to the µs scale allowed us to characterize the inhibition activity of (-)-epigallocatechin-3-gallate (EGCG) and curcumin (CUR) on unfolded amyloid fibrils. A reduced number of β-strands, characteristic of amyloid fibrils, and an increased distance between the amino acids that are responsible for the intra- and interprotein aggregations are observed. The central core region of the amyloid-β (Aβ(1-40)) fibril is found to have a high affinity to EGCG and CUR due to the presence of hydrophobic residues. Lastly, the free binding energy computed using the Poisson Boltzmann Surface Ares suggests that EGCG is more likely to bind to unfolded Aβ(1-40) fibrils and that this molecule can be a good candidate to develop new and more effective congeners to treat AD.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Brain; Catechin; Curcumin; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Dynamics Simulation; Peptide Fragments; Plaque, Amyloid; Protein Aggregates

Objectives Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease in which one of the most prominent pathological features is accumulation of amyloid (Aβ) plaques. This occurs due to the process of aggregation from monomeric to polymeric forms of Aβ peptide and thus represents one of the attractive targets to treat AD. Methods After initial evaluation of a set of molecules containing N-acetylpyrazoline moiety flanked by aromatic rings on both sides as Aβ aggregation inhibitors, the most potent molecules were further investigated for mechanistic insights. These were carried out by employing techniques such as circular dichroism (CD) spectroscopy, transmission electron microscopy (TEM), in vitro PAMPA-BBB (Blood-Brain Barrier) assay and cytotoxicity evaluation. Results Two molecules among the exploratory set displayed Aβ aggregation inhibition comparable to standard curcumin. Among the follow-up molecules, several molecules displayed more inhibition than curcumin. These molecules displayed good inhibitory activity even at lower concentrations. CD and TEM confirmed the mechanism of Aβ aggregation. These molecules were found to alleviate Aβ induced cytotoxicity. BBB penetration studies highlighted the potential of these molecules to reach central nervous system (CNS). Conclusions Thus, several promising Aβ-aggregation inhibitors were obtained as a result of this study.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Molecular Docking Simulation; Molecular Structure; Protein Aggregates; Protein Aggregation, Pathological; Pyrazoles; Rats

Curcumin and related compounds have been validated to remove even well-developed human β-amyloid plaques from the brain of transgenic mice, in vivo. However, their molecular mechanism of the plaque buster activity is rather unknown. Computational chemistry was employed here to better understand the β-amyloid protein elimination. According to our docking studies, a tautomeric "keto-enol" flip-flop mechanism is proposed that may chop up β-amyloid plaques in Alzheimer's due to removing each hairpin-foldamers one by one from both ends of aggregated fibrils. According to the experimented models, other bi-stable "keto-enol" pharmacophores might be identified to break up amyloid plaques and enhance rapid clearance of toxic aggregates in Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Curcumin; Dietary Supplements; Humans; In Vitro Techniques; Mice; Mice, Transgenic; Molecular Docking Simulation; Phytotherapy; Plaque, Amyloid; Protein Aggregates; Protein Aggregation, Pathological; Protein Binding

The amyloid plaques are a key hallmark of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Amyloidogenesis is a complex long-lasting multiphase process starting with the formation of nuclei of amyloid peptides: a process assigned as a primary nucleation. Curcumin (CU) is a well-known inhibitor of the aggregation of amyloid-beta (Aβ) peptides. Even more, CU is able to disintegrate preformed Aβ firbils and amyloid plaques. Here, we simulate by molecular dynamics the primary nucleation process of 12 Aβ peptides and investigate the effects of CU on the process. We found that CU molecules intercalate among the Aβ chains and bind tightly to them by hydrogen bonds, hydrophobic, π-π, and cation-π interactions. In the presence of CU, the Aβ peptides form a primary nucleus of a bigger size. The peptide chains in the nucleus become less flexible and more disordered, and the number of non-native contacts and hydrogen bonds between them decreases. For comparison, the effects of the weaker Aβ inhibitor ferulic acid (FA) on the primary nucleation are also examined. Our study is in good agreement with the observation that taken regularly, CU is able to prevent or at least delay the onset of neurodegenerative disorders.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Binding Sites; Coumaric Acids; Curcumin; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Molecular Dynamics Simulation; Neuroprotective Agents; Protein Aggregates; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs

This study has been carried out to obtain the thermochemical parameters of drugs used for Alzheimer's disease. The measurement of gas-phase basicity (GB) and proton affinity (PA) values of four important and commercially available drugs for Alzheimer's disease namely, rivastigmine, galantamine, memantine, and tacrine, is attempted for the first time. This study also includes the measurement of GB and PA values for the proposed drug curcumin, a natural product. We calculated the GB and PA values for all these drugs by applying electrospray ionization tandem mass spectrometry (ESI-MS/MS) with the extended kinetic method. Since, all these drugs possessing amino groups (basic nature), the PA values for all these drugs are high i.e., the PA values range from 923.6 to 979.7 kJ/mol and the GB values range from 886.2 to 943.3 kJ/mol. The GB and PA values obtained from the mass spectrometric experiments are well supported with the theoretical calculations. A high-level theoretical B3LYP/6-311 + G(d,p) method is used for the PA and GB calculation and the deviations are in the acceptable range.

Topics: Alzheimer Disease; Curcumin; Galantamine; Humans; Neuroprotective Agents; Protons; Rivastigmine; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

There is an increased need of drugs with multifunctional properties for visualization of β-amyloid (Aβ) plaques for early diagnosis and treatment of Alzheimer's disease (AD). Curcumin (Cur) is a potent antiamyloid, antiinflammatory, and antiapoptotic natural product that has been used to treat several neurodegenerative diseases, including AD. Curcumin can reduce amyloid burden, rescue neuronal damage, and restore normal cognitive and sensory motor functions in AD. Curcumin is a promising natural product theranostic because it fluoresces and preferentially binds to misfolded Aβ. However, poor water solubility, limited bioavailability, and inability to cross the blood-brain barrier (BBB) limit curcumin use for biological applications. In this work, ultrasmall (~ 11 nm) curcumin encapsulated Pluronic F127 nanoparticles (FCur NPs) were developed and optimized to enhance bioavailability, facilitate circulation in the bloodstream, and improve BBB penetration. We compare BBB crossing ability of FCur NPs and free curcumin using an in vitro BBB model, and we demonstrate brain accumulation following intravenous administration to healthy mice. FCur NPs display 6.5-fold stronger fluorescent intensity in the brain than those from free curcumin. In addition, in vitro comparison with Congo red, a marker for Aβ plaques, revealed that encapsulated curcumin maintains its ability to bind to Aβ plaques. FCur NPs exhibited antioxidant and antiapoptotic activity when compared to free curcumin. The combination of in vitro and in vivo results suggest potential utility of the inexpensive FCur NPs as a theranostic agent for AD.

Topics: Alzheimer Disease; Animals; Curcumin; Mice; Nanoparticles; Poloxamer; Precision Medicine

One new bisabolane-type sesquiterpenoid, together with four known bisabolane-type sesquiterpenoid derivatives and seven phenolics, was isolated from the rhizomes of Curcuma longa. Their structures were elucidated by extensive spectroscopic (IR, HR-ESI-MS, and NMR) data analysis. The possible anti-Alzheimer's disease (AD) activities of the isolated compounds were also evaluated using Caenorhabditis elegans AD pathological model, and 1β-hydroxybisabola-2,10-dien-4-one had the highest possible anti-AD activity.

Topics: Alzheimer Disease; Animals; Caenorhabditis elegans; Curcuma; Disease Models, Animal; Dose-Response Relationship, Drug; Molecular Structure; Monocyclic Sesquiterpenes; Phenols; Rhizome; Structure-Activity Relationship

A series of 4'-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound 8n demonstrated the best inhibitory effects on self-induced Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Cell Line; Cholinesterase Inhibitors; Drug Design; Drug Discovery; Electrophorus; Flurbiprofen; Humans; Mannich Bases; Molecular Docking Simulation; Peptide Fragments; Protein Aggregates; Rats; Swine

To target the multi-facets of Alzheimer's disease (AD), a series of novel GSK-3β inhibitors containing the 2,3-diaminopyridine moiety were designed and synthesized. The amide derivatives 5a-f showed moderate potency against GSK-3β with weak Cu

Topics: Alzheimer Disease; Amides; Amines; Animals; Antioxidants; Blood-Brain Barrier; Cell Line; Chelating Agents; Drug Design; Glycogen Synthase Kinase 3 beta; Humans; PC12 Cells; Protein Aggregation, Pathological; Protein Kinase Inhibitors; Rats; Structure-Activity Relationship; tau Proteins

2-(piperazin-1-yl)N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides are described as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and amyloid β aggregation inhibitors. Formation of synthesized compounds (P1P9) was justified via H

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Carboxylic Ester Hydrolases; Chelating Agents; Cholinesterase Inhibitors; Copper; Crystallography, X-Ray; Drug Evaluation, Preclinical; Humans; Inhibitory Concentration 50; Microscopy, Electron, Transmission; Molecular Docking Simulation; Pyrazoles; Pyridines; Spectrometry, Fluorescence

In an attempt to construct potential anti-Alzheimer's agents Naphthalene-triazolopyrimidine hybrids were synthesized and screened in vitro against the two cholinesterases (ChE)s, amyloid β aggregation and for antioxidation activity. Single-crystal X-ray crystallography was utilized for crystal structure determination of one of the compounds. In vitro study of compounds revealed that most of the compounds are capable of inhibiting acetylcholinesterase and Butyrylcholinesterase activity. Particularly, the compounds 4e and 4d exhibited IC

Topics: Alzheimer Disease; Anti-Anxiety Agents; Drug Design; Humans; Naphthalenes

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of chalcone-O-carbamate derivatives was designed and synthesized based on the multitarget-directed ligands strategy. The in vitro biological activities were evaluated including AChE/BChE inhibition, MAO-A/MAO-B inhibition, antioxidant activities, Aβ

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Butyrylcholinesterase; Chalcones; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Eels; Female; Horses; Humans; Male; Maze Learning; Mice; Mice, Inbred Strains; Models, Molecular; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Peptide Fragments; Protein Aggregates; Rats; Structure-Activity Relationship

A series of novel chalcone derivatives was designed, synthesized and evaluated as multifunctional agents for the treatment of AD. Among of these synthesized compounds, compound TM-2 was a selective BuChE inhibitor (IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Chalcone; Cholinesterase Inhibitors; Drug Design; Eels; Horses; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Peptide Fragments; Protein Aggregates

A series of novel chalcone-O-alkylamine derivatives were designed, synthesized and evaluated as multifunctional anti-Alzheimer's disease agents. Based on the experimental results, compound 23c exhibited good inhibitory potency on both acetylcholinesterase (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Biological Transport; Blood-Brain Barrier; Butyrylcholinesterase; Chalcones; Chelating Agents; Cholinesterase Inhibitors; Coordination Complexes; Copper; Drug Design; Female; Humans; Male; Memory Disorders; Mice; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Protein Binding; Scopolamine; Structure-Activity Relationship

Curcumin has been of interest in the field of Alzheimer's disease. Early studies on transgenic mice showed promising results in the reduction of amyloid plaques.However, curcumin is very poorly soluble in aqueous solutions and not easily accessible to coupling as it contains only phenolic groups as potential coupling sites. For these reasons only few imaging studies using curcumin bound as an ester were performed and curcumin is mainly used as nutritional supplement.. In the present study we produced an aminoethyl ether derivative of curcumin using a nucleophilic substitution reaction. This is a small modification and should not impact the properties of curcumin while introducing an easily accessible reactive amino group. This novel compound could be used to couple curcumin to other molecules using the standard methods of peptide synthesis. We studied the aminoethyl-curcumin compound and a tripeptide carrying this aminoethyl-curcumin and the fluorescent dye fluorescein (FITC-curcumin) in vitro on cell culture using confocal laser scanning microscopy and flow cytometry. Then these two substances were tested ex vivo on brain sections prepared from transgenic mice depicting Alzheimer-like β-amyloid plaques.. In the in vitro CLSM microscopy and flow cytometry experiments we found dot-like unspecific uptake and only slight cytotoxicity correlating with this uptake. As these measurements were optimized for the use of fluorescein as dye we found that the curcumin at 488nm fluorescence excitation was not strong enough to use it as a fluorescence marker in these applications. In the ex vivo sections CLSM experiments both the aminoethyl-curcumin and the FITC-curcumin peptide bound specifically to β- amyloid plaques.. In conclusion we successfully produced a novel curcumin derivative which could easily be coupled to other imaging or therapeutic molecules as a sensor for amyloid plaques.

Topics: Alzheimer Disease; Animals; Brain; Cell Line; Curcumin; Flow Cytometry; Fluorescein; Fluorescent Dyes; Humans; Mice, Transgenic; Microscopy, Confocal; Plaque, Amyloid

Curcumin, a compound found in Indian yellow curry, is known to possess various biological activities, including anti-oxidant, anti-inflammatory, and anti-cancer activities. Cur2004-8 is a synthetic curcumin derivative having symmetrical bis-alkynyl pyridines that shows a strong anti-angiogenic activity. In the present study, we examined the effect of dietary supplementation with Cur2004-8 on response to environmental stresses and aging using Caenorhabditis elegans as a model system. Dietary intervention with Cur2004-8 significantly increased resistance of C. elegans to oxidative stress. Its anti-oxidative-stress effect was greater than curcumin. However, response of C. elegans to heat stress or ultraviolet irradiation was not significantly affected by Cur2004-8. Next, we examined the effect of Cur2004-8 on aging. Cur2004-8 significantly extended both mean and maximum lifespan, accompanying a shift in time-course distribution of progeny production. Age-related decline in motility was also delayed by supplementation with Cur2004-8. In addition, Cur2004-8 prevented amyloid-beta-induced toxicity in Alzheimer's disease model animals which required a forkhead box (FOXO) transcription factor DAF-16. Dietary supplementation with Cur2004-8 also reversed the increase of mortality observed in worms treated with high-glucose-diet. These results suggest that Cur2004-8 has higher anti-oxidant and anti-aging activities than curcumin. It can be used for the development of novel anti-aging product.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Caenorhabditis elegans; Catechols; Curcumin; Dietary Supplements; Disease Models, Animal; Longevity; Molecular Structure; Oxidative Stress

Alzheimer's disease (AD) is the most common form of dementia and its prevention and treatment is a worldwide issue. Many natural components considered to be effective against AD have been identified. However, almost all clinical trials of these components for AD reported inconclusive results. We thought that multiple factors such as amyloid β (Aβ) and tau progressed the pathology of AD and that a therapeutic effect would be obtained by using multiple active ingredients with different effects. Thus, in this study, we treated ferulic acid (FA), phosphatidylserine (PS) and curcumin (Cur) in combination or alone to APPswe/PS1dE9 transgenic mice and evaluated cognitive function by Y-maze test. Consequently, only the three-ingredient group exhibited a significant improvement in cognitive function compared to the control group. In addition, we determined the amounts of Aβ, brain-derived neurotrophic factor (BDNF), interleukin (IL)-1β, acetylcholine and phosphorylated tau in the mouse brains after the treatment. In the two-ingredient (FA and PS) group, a significant decrease in IL-1β and an increasing trend in acetylcholine were observed. In the Cur group, significant decreases in Aβ and phosphorylated tau and an increasing trend in BDNF were observed. In the three-ingredient group, all of them were observed. These results indicate that the intake of multiple active ingredients with different mechanisms of action for the prevention and treatment of AD.

Topics: Acetylcholine; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Brain-Derived Neurotrophic Factor; Cognition; Coumaric Acids; Curcumin; Drug Therapy, Combination; Interleukin-1beta; Mice, Transgenic; Neuroprotective Agents; Phosphatidylserines; Presenilin-1; tau Proteins

Alzheimer's disease (AD) is a devastating neurodegenerative disease with no cure currently available. A pathological hallmark of AD is accumulation and deposition of amyloid-β protein (Aβ), a ∼4 kDa peptide generated through serial cleavage of the amyloid-β protein precursor (AβPP) by β- and γ-secretases. Curcumin is a natural compound primarily found in the widely used culinary spice, turmeric, which displays therapeutic potential for AD. Recently, we reported the development of curcumin analogs and identified a lead compound, curcumin-like compound-R17 (CLC-R17), that significantly attenuates Aβ deposition in an AD transgenic mouse model. Here, we elucidated the mechanisms of this analog on Aβ levels and AβPP processing using cell models of AD. Using biochemical methods and our recently developed nanoplasmonic fiber tip probe technology, we showed that the lead compound potently lowers Aβ levels in conditioned media and reduces oligomeric amyloid levels in the cells. Furthermore, like curcumin, the lead compound attenuates the maturation of AβPP in the secretory pathway. Interestingly, it upregulated α-secretase processing of AβPP and inhibited β-secretase processing of AβPP by decreasing BACE1 protein levels. Collectively, our data reveal mechanisms of a promising curcumin analog in reducing Aβ levels, which strongly support its development as a potential therapeutic for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Autophagy; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Curcumin; Humans

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antidepressive Agents; Antioxidants; Behavior Rating Scale; Catalase; Curcumin; Depression; Disease Models, Animal; Hippocampus; Inflammation; Male; Mice; Nanocapsules; Oxidative Stress; Peptide Fragments; Prefrontal Cortex; Superoxide Dismutase

Deposition of amyloid beta protein (Aβ) in extra- and intracellular spaces is one of the hallmark pathologies of Alzheimer's disease (AD). Therefore, detection of the presence of Aβ in AD brain tissue is a valuable tool for developing new treatments to prevent the progression of AD. Several classical amyloid binding dyes, fluorochrome, imaging probes, and Aβ-specific antibodies have been used to detect Aβ histochemically in AD brain tissue. Use of these compounds for Aβ detection is costly and time consuming. However, because of its intense fluorescent activity, high-affinity, and specificity for Aβ, as well as structural similarities with traditional amyloid binding dyes, curcumin (Cur) is a promising candidate for labeling and imaging of Aβ plaques in postmortem brain tissue. It is a natural polyphenol from the herb Curcuma longa. In the present study, Cur was used to histochemically label Aβ plaques from both a genetic mouse model of 5x familial Alzheimer's disease (5xFAD) and from human AD tissue within a minute. The labeling capability of Cur was compared to conventional amyloid binding dyes, such as thioflavin-S (Thio-S), Congo red (CR), and Fluoro-jade C (FJC), as well as Aβ-specific antibodies (6E10 and A11). We observed that Cur is the most inexpensive and quickest way to label and image Aβ plaques when compared to these conventional dyes and is comparable to Aβ-specific antibodies. In addition, Cur binds with most Aβ species, such as oligomers and fibrils. Therefore, Cur could be used as the most cost-effective, simple, and quick fluorochrome detection agent for Aβ plaques.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Coloring Agents; Curcumin; Disease Models, Animal; Humans; Mice; Plaque, Amyloid

Because old age is the greatest risk factor for dementia, a successful therapy will require an understanding of the physiological changes that occur in the brain with aging. Here, two structurally distinct Alzheimer's disease (AD) drug candidates, CMS121 and J147, were used to identify a unique molecular pathway that is shared between the aging brain and AD. CMS121 and J147 reduced cognitive decline as well as metabolic and transcriptional markers of aging in the brain when administered to rapidly aging SAMP8 mice. Both compounds preserved mitochondrial homeostasis by regulating acetyl-coenzyme A (acetyl-CoA) metabolism. CMS121 and J147 increased the levels of acetyl-CoA in cell culture and mice via the inhibition of acetyl-CoA carboxylase 1 (ACC1), resulting in neuroprotection and increased acetylation of histone H3K9 in SAMP8 mice, a site linked to memory enhancement. These data show that targeting specific metabolic aspects of the aging brain could result in treatments for dementia.

Topics: Acetyl Coenzyme A; Acetyl-CoA Carboxylase; Acetylation; Aging; Alzheimer Disease; Animals; Brain; Curcumin; Humans; Memory; Mice; Mitochondria; Protein Processing, Post-Translational; Signal Transduction

Today, find a good and effective drug for improving the incidence of Alzheimer disease (AD) is a major concern among scientists. Many researchers have recently targeted curcumin, a yellow powder from Curcuma longa, as the useful source of anti-Alzheimer agent. Though this compound widely used since ancient times as food color and/or additive, currently some researchers believed that this compound can treat AD-affected brains. However, the accurate mechanism of action of curcumin in the treatment of AD is obscure. In the recently published paper by Bijari et al. this compound (or pigment) considered as the functional food to cure AD. Their paper aimed to prove evident for the anti-AD activity of curcumin, but I found several errors with this paper that should be corrected by the authors. All of my queries and concerns are listed in the main text of this letter.

Topics: Alzheimer Disease; Curcumin; Humans

Curcumin is a natural product with several anti-Alzheimer's disease (AD) neuroprotective properties. This study aimed to investigate the effects of curcumin on memory deficits, lactate content, and monocarboxylate transporter 2 (MCT2) in APP/PS1 mouse model of AD. APP/PS1 transgenic mice and wild-type (WT) C57BL/6J mice were used in the present study. Spatial learning and memory of the mice was detected using Morris water-maze test. Cerebral cortex and hippocampus lactate contents were detected using lactate assay. MCT2 expression in the cerebral cortex and hippocampus was examined by immunohistochemistry and Western blotting. Results showed that spatial learning and memory deficits were improved in curcumin-treated APP/PS1 mouse group compared with those in APP/PS1 mice group. Brain lactate content and MCT2 protein level were increased in curcumin-treated APP/PS1 mice than in APP/PS1 mice. In summary, our findings indicate that curcumin could ameliorate memory impairments in APP/PS1 mouse model of AD. This phenomenon may be at least partially due to its improving effect on the lactate content and MCT2 protein expression in the brain. Anat Rec, 302:332-338, 2019. © 2018 Wiley Periodicals, Inc.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Disease Models, Animal; Female; Lactic Acid; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Monocarboxylic Acid Transporters; Presenilin-1

The main factors of Alzheimer's disease (AD) are the cerebral accumulation and the formation of extracellular amyloid plaques. The Aβ peptides are highly able to accumulative and produce fibrils that are placed to form these plaques in the AD. The biological action and drug delivery properties of curcumin (Cur) nanoformulation in the Alzheimer's disease therapeutics can be developed by the altering surface of the Poly-lactide-co-glycolide (PLGA) polymer and encapsulation of selenium nanoparticles (Se NPs). The morphological structure, size distributions of nanospheres, chemical interactions between the polymer and nanoformulations of synthesized curcumin and Se NPs loaded PLGA nanospheres have been studied by using the techniques of analytical instruments. The microscopic and nano observation results of synthesized Cur loaded nanospheres are exhibited that the mono-dispersed distributions of particles with spherical shaped structure. The present drug delivery system of Cur loaded Se-PLGA nanospheres could be decreases the amyloid-β load in the brains samples of AD mice, and greatly cured the memory deficiency of the model mice. The specific binding of Cur loaded Se-PLGA nanospheres with Aβ plaques were visualized by fluorescence microscopic technique. Se-PLGA targeting delivery system to amyloid plaques might be providing the enhanced therapeutic efficacy in AD lesions, which was studied by using transgenic mice (5XFAD). In conclusion, Cur loaded Se-PLGA nanoformulation has been demonstrated that valued delivery system for the targeted delivery and effective way to treat AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Curcumin; Drug Delivery Systems; Mice; Nanoparticles; Nanospheres; Plaque, Amyloid; Polylactic Acid-Polyglycolic Acid Copolymer; Protein Aggregation, Pathological; Selenium

Alzheimer's disease is likely to be caused by copathogenic factors including aggregation of Aβ peptides into oligomers and fibrils, neuroinflammation, and oxidative stress. To date, no effective treatments are available, and because of the multifactorial nature of the disease, it emerges the need to act on different and simultaneous fronts. Despite the multiple biological activities ascribed to curcumin as neuroprotector, its poor bioavailability and toxicity limit the success in clinical outcomes. To tackle Alzheimer's disease on these aspects, the curcumin template was suitably modified and a small set of analogues was attained. In particular, derivative 1 turned out to be less toxic than curcumin. As evidenced by capillary electrophoresis and transmission electron microscopy studies, 1 proved to inhibit the formation of large toxic Aβ oligomers, by shifting the equilibrium toward smaller nontoxic assemblies and to limit the formation of insoluble fibrils. These findings were supported by molecular docking and steered molecular dynamics simulations which confirmed the superior capacity of 1 to bind Aβ structures of different complexity. Remarkably, 1 also showed in vitro anti-inflammatory and antioxidant properties. In summary, the curcumin-based analogue 1 emerged as multipotent compound worthy to be further investigated and exploited in the Alzheimer's disease multitarget context.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Curcumin; Dose-Response Relationship, Drug; Humans; Inflammation Mediators; Molecular Docking Simulation; Peptide Fragments; Prenylation; Protein Structure, Secondary; Protein Structure, Tertiary; Rats; Rats, Sprague-Dawley

Peripheral blood-derived macrophages isolated from Alzheimer's disease (AD) patients have earlier been reported to demonstrate ineffective phagocytosis of amyloid-beta compared to the age-matched control subjects. However, the mechanisms causing unsuccessful phagocytosis remain unclear. Oxidative stress and the presence of ApoEε4 allele has been reported to play a major role in the pathogenesis of AD, but the contribution of oxidative stress and ApoEε4 in macrophage dysfunction leading to ineffective Aβ phagocytosis needs to be analyzed. Aβ phagocytosis assay has been performed using FITC-labeled Aβ and analyzed using flow cytometry and confocal imaging in patient samples and in THP-1 cells. Oxidative stress in patient-derived macrophages was analyzed by assessing the DNA damage using comet assay. ApoE polymorphism was analyzed using sequence-specific PCR and Hixson & Vernier Restriction isotyping protocol. In this study, we have analyzed the patterns of phagocytic inefficiency of macrophages in Indian population with a gradual decline in the phagocytic potential from mild cognitive impairment (MCI) to AD patients. Further, we have shown that the presence of ApoEε4 allele might also have a possible effect on the phagocytosis efficiency of the macrophages. Here, we demonstrate for the first time that oxidative stress could affect the amyloid-beta phagocytic potential of macrophages and hence by alleviating oxidative stress using curcumin, an anti-oxidant could enhance the amyloid-beta phagocytic efficacy of macrophages of patients with AD and MCI, although the responsiveness to curcumin might depends on the presence or absence of APOEε4 allele. Oxidative stress contributes significantly to decreased phagocytosis of Aβ by macrophages. Moreover, the phagocytic inefficiency of macrophages was correlated to the presence of ApoEε4 allele. This study also found that the Aβ-phagocytic potential of macrophage gets significantly enhanced in curcumin-treated patient-derived macrophages.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Case-Control Studies; Cell Differentiation; Cognitive Dysfunction; Curcumin; DNA Damage; Endocytosis; Fluorescence; Humans; Lysosomes; Macrophages; Monocytes; Oxidative Stress; Phagocytosis; Polymorphism, Genetic; THP-1 Cells

The pathogenesis of Alzheimer's disease (AD) is involved in the aggregation of misfolded amyloid β (Aβ), which upregulates the activity of acetylcholinesterase (AChE), increases the production of reactive oxygen species (ROS), enhances neuroinflammation, and eventually leads to neuronal death. Therefore, compounds targeting these mechanisms may be candidates for multitarget drugs in AD treatment. We found that two quinoline derivatives, VB-030 and VB-037, markedly reduced Aβ aggregation and ROS levels in the thioflavin T biochemical assay and Tet-On Aβ-green fluorescent protein (GFP) 293 AD cell model. These compounds further improved neurite outgrowth, reduced AChE activity and upregulated the molecular chaperone heat shock protein family B [small] member 1 (HSP27), whereas knockdown of HSP27 counteracted the compounds' neuroprotective effects on the Tet-On Aβ-GFP SH-SY5Y AD neuronal model. Furthermore, VB-037 attenuated lipopolysaccharide (LPS)/interferon (IFN)-γ-induced activation of BV-2 microglial cells. In addition, VB-037 demonstrated its potential to diminish LPS/IFN-γ-induced upregulation of caspase 1 activity, expression of interleukin (IL)-1β, and active phosphorylation of mitogen-activated protein kinase 14 (P38), mitogen-activated protein kinase 8 (JNK), and Jun proto-oncogene, AP-1 transcription factor subunit (JUN) signalings, as well as improve cell viability in the Tet-On Aβ-GFP SH-SY5Y AD neuronal model. Our findings strongly indicate the potential of VB-037 for modifying AD progression by targeting multiple mechanisms, thereby offering a new drug development avenue for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line; Curcumin; HSP27 Heat-Shock Proteins; Humans; Inflammation Mediators; MAP Kinase Signaling System; Mice; Neuronal Outgrowth; p38 Mitogen-Activated Protein Kinases; Protein Aggregates; Proto-Oncogene Mas; Quinolines

Liposomes (lip) carrying pharmaceuticals have shown promise in their ability to advance the therapy for neurodegenerative diseases. However, the low nerve-targeting capacity and poor penetration rate of lip through the blood-brain barrier (BBB) are major hurdles to achieving successful treatment. Herein, we developed lip incorporating cardiolipin (CL) and phosphatidic acid (PA) to promote their capability against hyperphosphorylation of tau protein, and a transactivator of transcription (TAT) peptide to permeate the BBB for delivering nerve growth factor (NGF), rosmarinic acid (RA), curcumin (CURC) and quercetin (QU). We derived an optimization method to assess a better composition of phospholipids in the lip loaded with the four medicines. Experimental results revealed that this optimized lip increased the viability of SK-N-MC cells insulted with β-amyloid peptide (Aβ) fibrils and prevented Wistar rat brain from producing hyperphosphorylated tau. CL and PA and the grafted TAT peptide on the carrier surface improved the rescue efficiency by inhibiting Aβ deposition and reducing the expressions of phosphorylated extracellular signal-regulated protein kinase 1/2 (p-ERK1/2), c-Jun N-terminal protein kinase, p38, tau at serine 202 and caspase-3. The lip also enhanced the expressions of p-ERK5 and p-cyclic adenosine monophosphate response element-binding protein. The amalgamated activity of NGF, RA, CURC and QU, and the effect of charged CL/PA on Aβ deposits supported the therapeutic efficacy of lip. The optimized TAT-NGF-RA-CURC-QU-CL/PA-lip can be a capable drug delivery system to cross the BBB and protect Alzheimer's disease brains from tau hyperphosphorylation. STATEMENTS OF SIGNIFICANCE: The therapeutic efficiency of liposomes (lip) against neurodegenerative disorder depends on their nerve-targeting capacity and ability to permeate the blood-brain barrier (BBB). Lip was developed incorporating cardiolipin (CL) and phosphatidic acid (PA) to promote their target specificity against hyperphosphorylation of tau protein, and a transactivator of transcription (TAT) peptide to permeate the BBB. We have successfully derived an optimization method using a new mathematical expression for the first time to assess a better composition of phospholipids in lip loaded with nerve growth factor (NGF), rosmarinic acid (RA), curcumin (CURC) and quercetin (QU). The optimized TAT-NGF-RA-CURC-QU-CL/PA-lip efficaciously down-regulated the expressions of phosphorylated extracell

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Blood-Brain Barrier; Curcumin; Hippocampus; Humans; Liposomes; Nerve Growth Factor; Neurons; Quercetin; Rats; Rats, Wistar; tau Proteins; Trans-Activators

Topics: Alzheimer Disease; Biological Availability; Curcumin; Drug Compounding; Humans; Medicine, East Asian Traditional; Zingiberaceae

In this report, we demonstrate that half-curcuminoid could be a better scaffold for PET tracer development. F-CRANAD-101 was designed and found to show significant response to both soluble and insoluble Aβs in the fluorescent spectral tests. PET imaging results indicated that 14 month and 5 month old APP/PS1 AD mice had higher signals in the brain than age-matched wild type mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Curcumin; Mice; Mice, Transgenic; Microscopy, Fluorescence; Positron-Emission Tomography; Radiopharmaceuticals

Alzheimer's disease (AD) is the progressive development of fatal neurodegenerative diseases. Owing to the unclearness of the pathogenesis of AD and the failure of the drug to cross the blood-brain barrier (BBB), there is currently a lack of effective diagnostic and therapeutic approaches in the treatment of AD. The aim of this study was to design exosomes (Exo) as a specifically designed carrier able to carry curcumin (cur) to prevent neuronal death in vitro and in vivo to alleviate the AD symptoms. Our results demonstrated that Exo improved the solubility and bioavailability of cur and increased drug penetration across the BBB by specific active targeting between Exo, inheriting the lymphocyte function-associated antigen 1 (LFA-1) and endothelial intercellular adhesion molecule 1 (ICAM-1). Exosomes derived from curcumin-treated (primed) cells (Exo-cur) can better prevent the death of neurons in vitro and in vivo to relieve the symptoms of AD by inhibiting phosphorylation of the Tau protein through activating the AKT/GSK-3β pathway. Our results suggested that Exo-cur featured highly effective BBB-crossing via receptor-mediated transcytosis to access brain tissues and inhibited Tau phosphorylation, holding great potential in improving targeted drug delivery and the recovery of neuronal function in AD therapy.

Topics: Alzheimer Disease; Animals; Cognition; Curcumin; Disease Models, Animal; Drug Carriers; Exosomes; Glycogen Synthase Kinase 3 beta; Male; Mice; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; tau Proteins

Alzheimer's disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial phagocytosis of amyloid (Aβ). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 expression (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammatory gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Curc-lo coordinately restored tightly correlated relationships between these genes' expression levels, and decreased expression of genes characteristic of toxic pro-inflammatory M1 microglia (CD11b, iNOS, COX-2, IL1β). In contrast, very high dose curcumin did not show these effects, failed to clear amyloid plaques, and dysregulated gene expression relationships. Curc-lo stimulated microglial migration to and phagocytosis of amyloid plaques both in vivo and in ex vivo assays of sections of human AD brain and of mouse brain. Curcumin also reduced levels of miR-155, a micro-RNA reported to drive a neurodegenerative microglial phenotype. In conditions without amyloid (human microglial cells in vitro, aged wild-type mice), Curc-lo similarly decreased CD33 and increased TREM2. Like curcumin, anti-Aβ antibody (also reported to engage the Syk pathway, increase CD68, and decrease amyloid burden in human and mouse brain) increased TREM2 in APPsw mice and decreased amyloid in human AD sections ex vivo. We conclude that curcumin is an immunomodulatory treatment capable of emulating anti-Aβ vaccine in stimulating phagocytic clearance of amyloid by reducing CD33 and increasing TREM2 and TyroBP, while restoring neuroinflammatory networks implicated in neurodegenerative diseases.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain; Curcumin; Disease Models, Animal; Disease Progression; Gene Expression; Humans; Immunity, Innate; Membrane Glycoproteins; Mice; Mice, Transgenic; Microglia; Phagocytosis; Plaque, Amyloid; Receptors, Immunologic; Sialic Acid Binding Ig-like Lectin 3

The discovery of J147 represented a significant milestone in the treatment of age-related disorders, which was further augmented by the recent identification of mitochondrial ATP synthase as the therapeutic target. However, the underlying molecular events associated with the modulatory activity of J147 have remained unresolved till date. Herein, we present, for the first time, a dynamical approach to investigate the allosteric regulation of mATP synthase by J147, using a reliable human αγβ protein model. The highlight of our findings is the existence of the J147-bound protein in distinct structural associations at different MD simulation periods coupled with concurrent open↔close transitions of the β catalytic and α allosteric (ATP5A) sites as defined by Cα distances (d), TriCα (Θ) and dihedral (φ) angular parameters. Firstly, there was an initial pairing of the αγ subunits away from the β subunit followed by the formation of the 'non-catalytic' αβ pair at a distance from the γ subunit. Interestingly, J147-induced structural arrangements were accompanied by the systematic transition of the β catalytic site from a closed to an open state, while there was a concurrent transition of the allosteric site from an open α

Topics: Allosteric Regulation; Alzheimer Disease; Binding Sites; Catalytic Domain; Curcumin; Humans; Hydrazines; Mitochondria; Mitochondrial Proton-Translocating ATPases; Molecular Docking Simulation; Principal Component Analysis; Static Electricity; Thermodynamics

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is caused by accumulation of amyloid-β (Aβ) peptide and is associated with neurological abnormalities in learning and memory. The protective role of curcumin on nerve cells, along with a potent antioxidant and free radical scavenging activity, has been widely studied. However, its low bioavailability and limited transport ability across the blood-brain barrier are two major drawbacks of its application in the treatment of different neurodegenerative diseases. The present study was designed to improve the effectiveness of curcumin in the treatment of Aβ-induced cognitive deficiencies in a rat model of AD by loading it into nanostructured lipid carriers (NLCs). The accumulation rate of curcumin (505.76±38.4 ng/g-1 h) in rat brain, as well as its serum levels, were significantly increased by using curcumin-loaded NLCs. The effective role of NLCs for brain delivery of curcumin was confirmed by reduced oxidative stress parameters (ROS formation, lipid peroxidation, and ADP/ATP ratio) in the hippocampal tissue and improvement of spatial memory. Also, histopathological studies revealed the potential of Cur-NLCs in decreasing the hallmarks of Aβ in AD in the animal model. The result of studying the neuroprotective potential of Cur-NLC in both pre-treatment and treatment modes showed that loading curcumin in NLCs is an effective strategy for increasing curcumin delivery to the brain and reducing Aβ-induced neurological abnormalities and memory defects and that it can be the basis for further studies in the area of AD prevention and treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Brain; Cognition Disorders; Curcumin; Disease Models, Animal; Drug Carriers; Drug Delivery Systems; Free Radical Scavengers; Hippocampus; Lipids; Male; Nanostructures; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Sprague-Dawley; Tissue Distribution

A novel series of tacrine-bifendate (THA-DDB) conjugates (7a-e) were synthesized and evaluated as potential anti-Alzheimer's agents. These compounds showed potent cholinesterase and self-induced β-amyloid (Aβ) aggregation inhibitory activities. A Lineweaver-Burk plot and molecular modeling study showed that these compounds can target both catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE). The cytotoxicity of the conjugate 7d against PC12 and HepG2 cells and hepatotoxicity against human hepatocyte cell line (HL-7702) were found to be considerably less compared to THA. Moreover, treatment with 7d did not exhibit significant hepatotoxicity in mice. Finally, in vivo studies confirmed that 7d significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, 7d has high potential for the treatment of Alzheimer's disease and warrants further investigation.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Biphenyl Compounds; Cell Line; Chemical and Drug Induced Liver Injury; Cholinesterase Inhibitors; Cholinesterases; Cognition; Drug Design; Hep G2 Cells; Humans; Liver; Male; Mice, Inbred ICR; PC12 Cells; Rats; Tacrine

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Cell Line, Tumor; Cholinesterase Inhibitors; Coumarins; Dose-Response Relationship, Drug; Drug Design; Humans; Kinetics; Male; Mice; Mice, Inbred Strains; Models, Molecular; Molecular Structure; Peptide Fragments; Protein Aggregates; Range of Motion, Articular; Structure-Activity Relationship; Thiocarbamates

A series of 4'-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Blood-Brain Barrier; Cell Line; Cell Survival; Chalcones; Chelating Agents; Copper; Drug Design; Flurbiprofen; Humans; Lipopolysaccharides; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Nitric Oxide; Peptide Fragments; Recombinant Proteins; Structure-Activity Relationship

A novel series of quinoline-indole derivatives were synthesized and evaluated as multitarget-directed ligands for the treatment of Alzheimer's disease (AD). Biological evaluation revealed that the derivatives had multifunctional profiles including antioxidant effects, blood-brain barrier (BBB) penetration, biometal chelation, Aβ aggregation modulation, neurotrophic and neuroprotective properties. Moreover, several representative target derivatives demonstrated hippocampal cell proliferation in living adult mice by intracerebroventricular (icv) injection or oral administration. Further drug-like property analysis demonstrated that the optimized compound, 8d (WI-1758), had liver microsomal metabolic stability, was well tolerated (>2000 mg/kg), and had a rational pharmacokinetic profile, as well as an oral bioavailability of 14.1% and a positive log BB (-0.19) to cross the BBB in vivo. Pharmacodynamics studies demonstrated that chronic oral administration of 8d·HCl substantially ameliorated the cognitive and spatial memory deficits in APP/PS1 AD mice and noticeably reduced overall cerebral β-amyloid deposits.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Cell Proliferation; Drug Design; Hippocampus; Humans; Indoles; Ligands; Memory Disorders; Mice; Quinolines

A series of 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Benzylamines; Blood-Brain Barrier; Cholinesterase Inhibitors; Drug Design; Humans; Kinetics; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Permeability; Protein Aggregates; Recombinant Proteins; Structure-Activity Relationship; Thiazoles

Sarsasapogenin, an active ingredient in Rhizoma anemarrhenae, is a promising bioactive lead compound in the treatment of Alzheimer's disease. To search for more efficient anti-Alzheimer agents, a series of novel sarsasapogenin-triazolyl hybrids were designed, synthesized, and evaluated for their Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Anemarrhena; Animals; Apoptosis; Cell Line; Drug Design; Hippocampus; Humans; Male; Maze Learning; Mice; Neuroprotective Agents; Peptide Fragments; Protein Aggregates; Spirostans

The multifactorial nature of Alzheimer's disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A novel family of donepezil-butylated hydroxytoluene (BHT) hybrids were designed, synthesized and evaluated as multifunctional ligands against AD. The optimal compound 7d displayed a balanced multifunctional profile covering an intriguing acetylcholinesterase (AChE) inhibition (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Butylated Hydroxytoluene; Cell Line; Cholinergic Agents; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Indans; Mice; Molecular Structure; Neuroprotective Agents; PC12 Cells; Piperidines; Protein Aggregates; Rats; Structure-Activity Relationship

One of the pathologic hallmarks in Alzheimer's disease (AD) is extracellular senile plaques composed of amyloid-β (Aβ) fibrils. Blocking Aβ self-assembly or disassembling Aβ aggregates by small molecules would be potential therapeutic strategies to treat AD. In this study, we synthesized a series of rationally designed divalent compounds and examined their effects on Aβ fibrillization. A divalent amide (2) derived from two molecules of caffeic acid with a propylenediamine linker of ∼5.0 Å in length, which is close to the distance of adjacent β sheets in Aβ fibrils, showed good potency to inhibit Aβ(1-42) fibrillization. Furthermore, compound 2 effectively dissociated the Aβ(1-42) preformed fibrils. The cytotoxicity induced by Aβ(1-42) aggregates in human neuroblastoma was reduced in the presence of 2, and feeding 2 to Aβ transgenic C. elegans rescued the paralysis phenotype. In addition, the binding and stoichiometry of 2 to Aβ(1-40) were demonstrated by using electrospray ionization-traveling wave ion mobility-mass spectrometry, while molecular dynamic simulation was conducted to gain structural insights into the Aβ(1-40)-2 complex.

Topics: Alzheimer Disease; Amides; Amyloid beta-Peptides; Animals; Caenorhabditis elegans; Caffeic Acids; Humans; Models, Molecular; Peptide Fragments; Protein Multimerization

The 3-hydroxypyran-4-one moiety (maltol) was incorporated into the structure of resveratrol to achieve a series of resveratrol-maltol hybrids (8a-8k) as novel multi-target-directed ligands (MTDLs). In vitro biological evaluation of the MTDLs revealed these compounds to have a triple function, namely inhibition of self-induced Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Benzothiazoles; Chelating Agents; Dose-Response Relationship, Drug; Humans; Ligands; Molecular Structure; Neuroprotective Agents; Peptide Fragments; Protein Aggregates; Pyrones; Resveratrol; Structure-Activity Relationship; Sulfonic Acids

A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Butyrylcholinesterase; Chelating Agents; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Discovery; Humans; Models, Molecular; Molecular Structure; Peptide Fragments; Phthalimides; Protein Aggregates; Structure-Activity Relationship

The current study introduces a new idea of utilising several bio/chemoinformatics tools in comparing two bio-similar natural molecules viz. curcumin and bisdemethoxycurcumin (BDMC) in order to select a potential nose-to-brain remedy for Alzheimer disease. The comparison comprised several bio/chemo informatics tools. It encompassed all levels starting from loading the drug in a certain carrier; PLGA nanoparticles, to the biopharmaceutical level investigating the interaction with mucin and inhibition of P-gp blood-brain barrier efflux pumps. Finally, the therapeutic level was investigated by studying the interaction with pharmacological targets such as amyloid peptide plaques and cyclooxygenase2 enzyme responsible for the inflammatory reactions of the studied disease. The comparison revealed the superiority of curcumin over BDMC. Five new analogues were also hypothesised where diethoxybisdemethoxycurcumin was  recommended as a superior molecule. This work introduced the virtual utilisation of bio/chemo informatics tools as a reliable and economic alternative to the exhausting and resources-consuming wet-lab experimentation.

Topics: Alzheimer Disease; ATP Binding Cassette Transporter, Subfamily B; Brain; Computational Biology; Curcumin; Diarylheptanoids; Drug Carriers; Humans; Inflammation; Mucins; Nose

Topics: Alzheimer Disease; Antioxidants; Biological Availability; Brain; Calorimetry, Differential Scanning; Cell Line, Tumor; Crystallization; Curcumin; Drug Carriers; Humans; Micelles; Nanocomposites; Solubility; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction

Neuroinflammation and the presence of amyloid beta protein (Aβ) and neurofibrillary tangles are key pathologies in Alzheimer's disease (AD). As a potent anti-amyloid and anti-inflammatory natural polyphenol, curcumin (Cur) could be potential therapies for AD. Unfortunately, poor solubility, instability in physiological fluids, and low bioavailability limit its clinical utility. Recently, different lipid modifications in the formulae of Cur have been developed that would enhance its therapeutic potential. For example, we have reported greater permeability and neuroprotection with solid lipid curcumin particles (SLCP) than with natural Cur in an in vitro model of AD. In the present study, we compared the Aβ aggregation inhibition, anti-amyloid, anti-inflammatory responses of Cur and or SLCP in both in vitro and in vivo models of AD. One-year-old 5xFAD-and age-matched wild-type mice were given intraperitoneal injections of Cur or SLCP (50 mg/kg body weight) for 2- or 5-days. Levels of Aβ aggregation, including oligomers and fibril formation, were assessed by dot blot assay, while Aβ plaque load and neuronal morphology in the pre-frontal cortex (PFC) and hippocampus were assayed by immunolabeling with Aβ-specific antibody and cresyl violet staining, respectively. In addition, neuroinflammation was assessed the immunoreactivity (IR) of activated astrocytes (GFAP) and microglia (Iba-1) in different brain areas. Finally, comparisons of solubility and permeability of Cur and SLCP were made in cultured N2a cells and in primary hippocampal neurons derived from E16 pups of 5xFAD mice.. We observed that relative to Cur, SLCP was more permeable, labeled Aβ plaques more effectively, and produced a larger decrease in Aβ plaque loads in PFC and dentate gyrus (DG) of hippocampus. Similarly, relative to Cur, SLCP produced a larger decrease of pyknotic, or tangle-like, neurons in PFC, CA1, and CA3 areas of hippocampus after 5 days of treatment. Both Cur and or SLCP significantly reduced GFAP-IR and Iba-1-IR in PFC, in the striatum as well as CA1, CA3, DG, subicular complex of hippocampus, and the entorhinal cortex in the 5xFAD mice after 5 days of treatment.. The use of SLCP provides more anti-amyloid, anti-inflammatory, and neuroprotective outcomes than does Cur in the 5xFAD mouse model of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Curcumin; Disease Models, Animal; Hippocampus; Mice, Transgenic; Neurofibrillary Tangles; Neurons; Neuroprotective Agents; Plaque, Amyloid

BACKGROUND The aim of this study was to investigate the effect of curcumin treatment on the expression of the N-methyl-D-aspartate receptor (NMDAR) subunit, NR2A, in a rat PC12 cell line treated with the acetyl amyloid-β peptide, Aβ(25-35), in an in vitro model of Alzheimer's disease. MATERIAL AND METHODS PC12 cells, derived from rat phaeochromocytoma, were treated for 24 hours with increasing concentrations of curcumin (5, 10, 20, 30 µM/L) in the presence of the acetyl amyloid-β peptide, Aβ(25-35). A Cell Counting Kit-8 (CCK-8) assay was used to determine cell viability, and flow cytometry was used to measure cell apoptosis. In the supernatant of the treated PC12 cells, Western blotting was used to measure the cell injury biomarker, lactate dehydrogenase (LDH), and the biomarker for oxidative stress, malondialdehyde (MDA). Expression of the N-methyl-D-aspartate receptor (NMDAR) subunit, NR2A, was analyzed by Western blotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS Curcumin treatment protected the rat PC12 cells from Ab(25-35)-induced reduction in cell viability, apoptosis, release of LDH, and MDA production. Curcumin treatment of PC12 cells was associated with increased expression of the NMDAR subunit, NR2A. CONCLUSIONS The findings of this study showed a neuroprotective effect of curcumin treatment in an in vitro model of Alzheimer's disease that was associated with the increased expression of the NMDAR subunit, NR2A.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Caspase 3; Cell Survival; Curcumin; L-Lactate Dehydrogenase; Malondialdehyde; Models, Biological; PC12 Cells; Phosphorylation; Protein Subunits; Proto-Oncogene Proteins c-akt; Rats; Receptors, N-Methyl-D-Aspartate

The combined fluorescent and Aβ-binding properties of the dietary spice curcumin could yield diagnostic purpose in the search for a non-invasive Aβ-biomarker for Alzheimer's disease (AD). However, evidence on the binding properties of curcumin, its conjugates and clinically used bio-available formulations to AD neuropathological hallmarks is scarce. We therefore assessed the binding properties of different curcumin forms to different neuropathological deposits in post-mortem brain tissue of cases with AD, other neurodegenerative diseases, and controls. Post mortem brain tissue was histochemically assessed for the binding of curcumin, its isoforms, conjugates and bio-available forms and compared to routinely used staining methods. For this study we included brains of early onset AD, late onset AD, primary age-related tauopathy (PART), cerebral amyloid angiopathy (CAA), frontotemporal lobar degeneration (FTLD) with tau or TAR DNA-binding protein 43 (TDP-43) inclusions, dementia with Lewy bodies (DLB), Parkinson's disease (PD) and control cases without brain pathology. We found that curcumin binds to fibrillar amyloid beta (Aβ) in plaques and CAA. It does not specifically bind to inclusions of protein aggregates in FTLD-tau cases, TDP-43, or Lewy bodies. Curcumin isoforms, conjugates and bio-available forms show affinity for the same Aβ structures. Curcumin staining overlaps with immunohistochemical detection of Aβ in fibrillar plaques and CAA, and to a lesser extent cored plaques. A weak staining of neurofibrillary tangles was observed, while other structures immunopositive for phosphorylated tau remained negative. In conclusion, curcumin, its isoforms, conjugates and bio-available forms selectively bind fibrillar Aβ in plaques and CAA in post mortem AD brain tissue. Curcumin, being a food additive with fluorescent properties, is therefore an interesting candidate for in-vivo diagnostics in AD, for example in retinal fluorescent imaging.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Anti-Inflammatory Agents, Non-Steroidal; Autopsy; Brain; Cerebral Amyloid Angiopathy; Curcumin; DNA-Binding Proteins; Female; Frontotemporal Lobar Degeneration; Humans; Male; Middle Aged; Neurofibrillary Tangles; Plaque, Amyloid; Protein Binding; Retrospective Studies; tau Proteins; Tauopathies

Alzheimer's disease is a neurodegenerative disorder mainly characterized by β-amyloid deposit and tau hyperphosphorylation with no curative treatments. Curcumin (Cur) has been proved to have potential use in Alzheimer's disease with its anti-amyloid, anti-inflammatory, and anti-oxidant properties, etc. However, its hydrophobicity and low bioavailability hinder its application. In this paper, we designed a novel brain-target nanoparticle, poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-PEG) conjugated with B6 peptide and was loaded with Cur (PLGA-PEG-B6/Cur) and administered it into HT22 cells and APP/PS1 Al transgenic mice. The in vitro assays including dynamic light scattering (DLS), flow cytometry (FCM), red blood cell (RBC) lysis, and thromboelastography (TEG) analysis indicated that this nanoparticle could narrow the diameter of Cur, increase its cellular uptake and possess good blood compatibility. The results from Morris water maze proved that PLGA-PEG-B6/Cur could tremendously improve the spatial learning and memory capability of APP/PS1 mice, compared with native Cur. The ex vivo assays including Bielschowsky silver staining, immunostaining, and western blotting demonstrated that PLGA-PEG-B6/Cur could reduce hippocampal β-amyloid formation and deposit and tau hyperphosphorylation. Thus, we suggested that PLGA-PEG-B6/Cur nanoparticles would be of potential and promising use for the treatment of Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Biocompatible Materials; Biological Availability; Cell Line; Curcumin; Drug Carriers; Drug Compounding; Humans; Hydrophobic and Hydrophilic Interactions; Mice; Molecular Targeted Therapy; Nanoparticles; Oligopeptides; Polyesters; Polyethylene Glycols

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line; Cognitive Dysfunction; Copper; Curcumin; Disease Models, Animal; Drug Compounding; Humans; Hydrogen Peroxide; Male; Mice; Mice, Transgenic; Micelles; Nanostructures; Peptide Fragments

New dual electrochemical and fluorescence sensitive curcumin-graphene quantum dots sensing platform coated on the transparent Indium-Tin-Oxide electrode was developed to sense APOe4 DNA, responsible of Alzheimer's disease. Curcumin molecule with its dual fluorescence and electrochemical properties was electropolymerized on GQDs-ITO surface. EDC/NHS chemistry was used to covalently immobilize an amino-substituted DNA probe via a malonic acid spacer. Quenching of curcumin signals following hybridized DNA complex was employed to quantify APOe4 DNA. Amperometric studies revealed an ultrasensitive behavior toward the formation of DNA complex with a sensitivity of 4.74 nA.mL.pg

Topics: Alzheimer Disease; Apolipoprotein E4; Curcumin; Electrochemical Techniques; Fluorescence; Graphite; Humans; Particle Size; Quantum Dots; Spectrometry, Fluorescence

Amyloid β fibrillation is an early event in Alzheimer's disease, so its detection is important to understand its roles in Alzheimer's disease. Curcumin, which has poor water solubility, has been reported to have many pharmacological activities including potent anti-amyloid β fibril activity in Alzheimer's disease. In this study, we found that curcumin analogues with the fluorescence property instead of non-inhibition of amyloid β fibrils. The development of new curcumin analogue, Me-CUR (9), as fluorescent switchable probe to detect amyloid β fibrils is described. Me-CUR (9) shows excellent fluorescence, especially higher than ThT (4), in the presence of amyloid β fibrils. These results suggest that Me-CUR (9) can become a useful in vitro amyloid fluorescence sensor for diagnosis of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Curcumin; Drug Design; Fluorescent Dyes; Humans; Protein Binding; Spectrometry, Fluorescence

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive accumulation of amyloid-beta (Aβ) peptides in brain. In the present study, two familial Aβ42 mutations, namely A2V (harmful) and A2T (protective) have been analyzed and compared with the wild-type (WT) by performing all-atom molecular dynamics (MD) simulations in the absence and presence of curcumin, a well-known inhibitor of Aβ plaque formation. Mutant A2V was found to exhibit highest stability followed by WT and mutant A2T in the absence of curcumin. This stability trend was found to be reversed in the presence of curcumin, suggesting a significant change in the conformational landscape of Aβ42 folding. Due to significant differences in the folding and interaction patterns of the mutants A2V and A2T, curcumin exhibited higher binding affinity for mutant A2T as compared to that of A2V. To the best of our knowledge, this is the first report on the effect of curcumin binding on structural landscapes of the two contrasting point mutants providing an understanding of the basis of Aβ plaque formation and its prevention by curcumin.

Topics: Alzheimer Disease; Amino Acid Substitution; Amyloid beta-Peptides; Curcumin; Humans; Hydrophobic and Hydrophilic Interactions; Kinetics; Molecular Conformation; Molecular Dynamics Simulation; Mutation; Peptide Fragments; Protein Conformation

A novel series of donepezil based multi-functional agents "(E)-5,6-dimethoxy-2-(4-(4-substituted piperazin-1-yl)benzylidene)-2,3-dihydro-1H-inden-1-ones" have been designed and synthesized as potential anti-Alzheimer's agents. In-vitro studies revealed that these compounds demonstrated moderate to good AChE and Aβ aggregation inhibitory activity. These derivatives are also endowed with admirable antioxidant activity. Among the entire series compounds IP-9, IP-13 and IP-15 appeared as most active multi-functional agents and displayed marked AChE inhibitory, Aβ disaggregation and antioxidant activity. Studies indicate that IP-13 and IP-15 showed better AChE inhibitory activity than the standard drug donepezil and IP-9, IP-13 as well as IP-15 exhibited better Aβ aggregation inhibitory activity than curcumin. These compounds (IP-9, IP-13 and IP-15) successfully diminished H

Topics: Acetylcholine; Alzheimer Disease; Cell Line; Donepezil; Drug Delivery Systems; Drug Design; Humans; Indans; Ligands; Microscopy, Electron, Transmission; Molecular Dynamics Simulation; Molecular Structure; Neuroprotective Agents; Piperidines; Protein Aggregation, Pathological; Protein Binding

A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC

Topics: Acetylcholinesterase; Alzheimer Disease; Butyrylcholinesterase; Catalytic Domain; Cell Line, Tumor; Chalcones; Cholinesterase Inhibitors; Humans; Hydrogen Bonding; Kinetics; Molecular Docking Simulation; Molecular Dynamics Simulation; Oxidative Stress; Reactive Oxygen Species; Rivastigmine; Structure-Activity Relationship

A series of homoisoflavonoid Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease. It demonstrated that most of the derivatives were selective AChE and MAO-B dual inhibitors with good multifunctional properties. Among them, compound 10d displayed the comprehensive advantages, with excellent AChE and MAO-B inhibitory activities (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Isoflavones; Mannich Bases; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Structure-Activity Relationship

A series of aurone Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compound 7d exhibited outstanding inhibitory activity for RatAChE, EeAChE and HuAChE (IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Cholinesterase Inhibitors; Drug Design; Electrophorus; Humans; Mannich Bases; Neuroprotective Agents; PC12 Cells; Rats

A series of 4'-aminochalcone-revastigmine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. The results showed that most of these compounds exhibited good multifunctional activities. In particular, compound 6c displayed the best inhibitory potency on acetylcholinesterase (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Blood-Brain Barrier; Chalcones; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Rivastigmine; Structure-Activity Relationship; Swine

A series of deferiprone-resveratrol hybrids have been designed and synthesized as multitarget-directed ligands (MTDLs) through merging the chelating moiety 3-hydroxypyridin-4-one into the structure of resveratrol, a natural antioxidant agent and β-amyloid peptide (Aβ) aggregation inhibitor. The in vitro biological evaluation revealed that most of these newly synthesized compounds exhibited good inhibitory activity against self-induced Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Chelating Agents; Chemistry Techniques, Synthetic; Copper; Deferiprone; Drug Design; Iron; Molecular Docking Simulation; Peptide Fragments; Protein Aggregates; Protein Structure, Secondary; Pyridones; Resveratrol; Stilbenes; Structure-Activity Relationship

Alzheimer's disease (AD) is the main cause of dementia in people over 65 years. One of the major culprits in AD is the self-aggregation of amyloid-β peptide (Aβ), which has stimulated the search for small molecules able to inhibit Aβ aggregation. In this context, we recently reported a simple, but effective in vitro cell-based assay to evaluate the potential antiaggregation activity of putative Aβ aggregation inhibitors. In this work this assay was used together with docking and molecular dynamics simulations to analyze the anti-Aβ aggregation activity of several naturally occurring flavonoids and phenolic compounds. The results showed that rosmarinic acid, melatonin, and o-vanillin displayed zero or low inhibitory capacity, curcumin was found to have an intermediate inhibitory potency, and apigenin and quercetin showed potent antiaggregation activity. Finally, the suitability of the combined in vitro cell-based/in silico approach to distinguish between active and inactive compounds was further assessed for an additional set of flavonols and dihydroflavonols.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Apigenin; Benzaldehydes; Cinnamates; Depsides; Flavonoids; Humans; In Vitro Techniques; Molecular Structure; Peptide Fragments; Phenols; Quercetin; Rosmarinic Acid

Considering the complex etiology of Alzheimer's disease (AD), multifunctional agents may be beneficial for the treatment of this disease. A series of DL-3-n-butylphthalide-Edaravone hybrids were designed, synthesized and evaluated as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases. Among them, compounds 9a-d exhibited good inhibition of self-induced Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Antipyrine; Benzofurans; Binding Sites; Blood-Brain Barrier; Edaravone; Humans; Hydrogen Bonding; Inhibitory Concentration 50; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Protein Binding; Protein Structure, Tertiary

The aggregation of amyloid-β peptides into cytotoxic oligomeric and fibrillary aggregates is believed to be one of the major pathological events in Alzheimer disease. Here we report the design and synthesis of a novel series of indole and 7-azaindole derivatives containing, nitrile, piperidine and N-methyl-piperidine substituents at the 3-position to prevent the pathological self-assembly of amyloid-β. We have further demonstrated that substitution of the azaindole and indole derivatives at the 3 positions is required to obtain compounds with improved physicochemical properties to allow brain penetration.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Drug Discovery; Humans; Indoles; Liver; Male; Mice; Peptide Fragments

A series of 1-hydroxyl-3-aminoalkoxy-thioxanthone derivatives were designed, synthesized and evaluated as potential multifunctional agents against Alzheimer's disease (AD). The results indicated that most of these compounds exhibited good AChE and MAOs inhibitory activities, significant inhibition of self- and Cu

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Cell Line; Cholinesterase Inhibitors; Humans; Kinetics; Models, Molecular; Monoamine Oxidase Inhibitors; Thioxanthenes; Xanthones

A series of 2-arylethenyl-N-methylquinolinium derivatives were designed and synthesized based on our previous research of 2-arylethenylquinoline analogues as multifunctional agents for the treatment of Alzheimer's disease (AD) (Eur. J. Med. Chem. 2015, 89, 349-361). The results of in vitro biological activity evaluation, including β-amyloid (Aβ) aggregation inhibition, cholinesterase inhibition, and antioxidant activity, showed that introduction of N-methyl in quinoline ring significantly improved the anti-AD potential of compounds. The optimal compound, compound a12, dramatically attenuated the cell death of glutamate-induced HT22 cells by preventing the generation of ROS and increasing the level of GSH. Most importantly, intragastric administration of a12•HAc was well tolerated at doses up to 2000 mg/kg and could traverse blood-brain barrier.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Blood-Brain Barrier; Cell Death; Cell Line; Cholinesterase Inhibitors; Drug Design; Glutathione; Humans; Quinolines; Reactive Oxygen Species

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Coumaric Acids; Drug Design; Eels; Humans; Memory Disorders; Mice; PC12 Cells; Rats

A novel series of feruloyl-donepezil hybrid compounds were designed, synthesized and evaluated as multitarget drug candidates for the treatment of Alzheimer's Disease (AD). In vitro results revealed potent acetylcholinesterase (AChE) inhibitory activity for some of these compounds and all of them showed moderate antioxidant properties. Compounds 12a, 12b and 12c were the most potent AChE inhibitors, highlighting 12a with IC

Topics: Acrylates; Alzheimer Disease; Animals; Anti-Inflammatory Agents; Antioxidants; Cell Line; Cells, Cultured; Cholinesterase Inhibitors; Donepezil; Drug Design; Humans; Indans; Male; Mice; Molecular Docking Simulation; Molecular Targeted Therapy; Neurons; Neuroprotective Agents; Piperidines; Structure-Activity Relationship

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Cell Survival; Cholinesterase Inhibitors; Donepezil; Drug Design; Electrophorus; Humans; Indans; Mice; Molecular Docking Simulation; Neuroprotective Agents; PC12 Cells; Peptide Fragments; Piperidines; Protein Aggregates; Pyridinium Compounds; Rats; Structure-Activity Relationship

A series of scutellarein-O-acetamidoalkylbenzylamines derivatives were designed based on a multitarget-directed ligands strategy for the treatment of Alzheimer's disease. Among these compounds, compound T-22 demonstrated excellent acetylcholinesterase inhibitory, moderate inhibitory effects on self-induced Aβ

Topics: Alzheimer Disease; Animals; Cell Line, Tumor; Cell Survival; Cholinesterase Inhibitors; Cholinesterases; Dose-Response Relationship, Drug; Drug Design; Flavones; Humans; Maze Learning; Mice; Mice, Inbred Strains; Models, Molecular; Molecular Structure; PC12 Cells; Rats; Scopolamine; Structure-Activity Relationship

In our endeavor towards the development of potent multitarget ligands for the treatment of Alzheimer's disease, a series of triazine-triazolopyrimidine hybrids were designed, synthesized and characterized by various spectral techniques. Docking and scoring techniques were used to design the inhibitors and to display their interaction with key residues of active site. Organic synthesis relied upon convergent synthetic routes were mono and di-substituted triazines were connected with triazolopyrimidine using piperazine as a linker. In total, seventeen compounds were synthesized in which the di-substituted triazine-triazolopyrimidine derivatives 9a-d showed better acetylcholinesterase (AChE) inhibitory activity than the corresponding tri-substituted triazine-triazolopyrimidine derivatives 10a-f. Out of the disubstituted triazine-triazolopyrimidine based compounds, 9a and 9b showed encouraging inhibitory activity on AChE with IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Electrophorus; Horses; Molecular Structure; Pyrimidines; Structure-Activity Relationship; Triazines

In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer's disease (AD), a series of chromone derivatives were designed, synthesized and evaluated. In vitro assay indicated that most of the target compounds have both MAOs inhibition activities, antioxidant activity and biometal chelating ability. Especially, compound s19 exhibits good inhibitory potency for inhibition of MAOs (IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Apoptosis; Binding Sites; Blood-Brain Barrier; Chromones; Copper; Humans; Hydrogen Peroxide; Inhibitory Concentration 50; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Protein Structure, Tertiary; Rats; Reactive Oxygen Species; Structure-Activity Relationship

A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-β (Aβ) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Survival; Coumarins; Dose-Response Relationship, Drug; Drug Design; Humans; Male; Mice; Mice, Inbred Strains; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pargyline; PC12 Cells; Protein Aggregates; Rats; Structure-Activity Relationship

Combining N-benzyl pyridinium moiety and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activities were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for ChE and Aβ (1-42) self-aggregation, and clearly selective inhibition to MAO-B over MAO-A. Of these compounds, compound 7f was the most potent inhibitor for hMAO-B, and it was also a good and balanced inhibitor to ChEs and hMAO-B (0.0373 μM for eeAChE; 2.32 μM for eqBuChE; 1.57 μM for hMAO-B). Molecular modeling and kinetic studies revealed that compound 7f was a mixed-type inhibitor, which bond simultaneously to CAS and PAS of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, compound 7f with no toxicity on PC12 neuroblastoma cells, showed good ability to inhibit Aβ (1-42) self-aggregation and cross the BBB. Collectively, all these results suggested that compound 7f might be a promising multi-target lead candidate worthy of further pursuit.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholinesterase Inhibitors; Coumarins; Dose-Response Relationship, Drug; Drug Design; Humans; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; PC12 Cells; Protein Aggregates; Pyridinium Compounds; Rats; Structure-Activity Relationship

By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a novel series of cinnamamide-dibenzylamine hybrids have been designed, synthesized, and evaluated biologically. In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit ChEs, strong potency inhibitory of self-induced β-amyloid (Aβ) aggregation and to act as potential antioxidants and biometal chelators. A Lineweaver-Burk plot and molecular modeling study showed that compound 7f targeted both the CAS and PAS of AChE. In addition, compound 7f could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Overall, all of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7f as the lead structure worthy of further investigation.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Benzylamines; Blood-Retinal Barrier; Butyrylcholinesterase; Cell Death; Cholinergic Agents; Cholinesterase Inhibitors; Cinnamates; Dose-Response Relationship, Drug; Humans; Molecular Structure; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Rats; Structure-Activity Relationship

A series of multitarget ligands was designed by introducing several structurally diverse aminoacetamide groups at position 6 of the deoxyvasicinone group, with the aim of obtaining novel multifunctional anti-Alzheimer's disease agents using deoxyvasicinone as the substrate. In vitro studies showed that almost all of the derivatives were potent inhibitors of human recombinant acetylcholinesterase (hAChE) and human serum butyrylcholinesterase (hBChE), with IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Kinetics; Ligands; Molecular Structure; Peptide Fragments; Protein Aggregates; Quinazolines; Structure-Activity Relationship

Starting from nature as original source, new potential agents with pleiotropic activities have been synthesized and evaluated as neuroprotective agents. In this work, novel nature-based hybrids, combining antioxidant motifs with rivastigmine, have been designed and synthesized. The biological results revealed that the new compounds inhibit both AChE and BuChE. In particular, lipoic acid hybrids LA1, LA2, LA3 resulted to be the most potent inhibitors of BuChE showing IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Biological Products; Butyrylcholinesterase; Cell Death; Cell Line, Tumor; Cell Survival; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Free Radical Scavengers; Glutamic Acid; Humans; Molecular Structure; Neuroprotective Agents; Peptide Fragments; Protein Aggregates; Rivastigmine; Structure-Activity Relationship

The formation of extracellular aggregates built up by deposits of β-amyloid (Aβ) is a hallmark of Alzheimer's disease (AD). Curcumin has been reported to display anti-amyloidogenic activity, not only by inhibiting the formation of new Aβ aggregates, but also by disaggregating existing ones. However, the uptake of Curcumin into the brain is severely restricted by its low ability to cross the blood-brain barrier (BBB). Therefore, novel strategies for a targeted delivery of Curcumin into the brain are highly desired. Here, we encapsulated Curcumin as active ingredient in PLGA (polylactide-co-glycolic-acid) nanoparticles (NPs), modified with g7 ligand for BBB crossing. We performed in depth analyses of possible toxicity of these NPs, uptake, and, foremost, their ability to influence Aβ pathology in vitro using primary hippocampal cell cultures. Our results show no apparent toxicity of the formulated NPs, but a significant decrease of Aβ aggregates in response to Curcumin loaded NPs. We thus conclude that brain delivery of Curcumin using BBB crossing NPs is a promising future approach in the treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biological Transport; Blood-Brain Barrier; Curcumin; Humans; Nanoparticles

Considerable evidence shows critical roles of intracellular pathogenic events of Alzheimer's disease (AD). In particular, intracellular amyloid-β accumulation and oligomerization are early AD pathologic processes, which may lead to changes in inflammatory molecules and other AD-related pathological components. Curcumin and its analogs have been identified as potential drug candidates for AD. However, the effects of curcumin on intracellular AD pathologic processes remain largely unknown. Here we utilized a recently developed nanoplasmonic fiber tip probe (nFTP) technology and investigated whether curcumin leads to intracellular AD pathologic changes. We showed that our nFTP technology could robustly detect intracellular AD-related protein changes caused by a well-known inflammation inducer and a familial AD mutation. Intriguingly, curcumin remarkably reduced the level of intracellular oligomers while modestly reduced the level of an inflammatory cytokine. Thus, our results provided evidence that curcumin's mechanism of action in attenuating AD pathology is through a major role of decreasing oligomerization.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cells, Cultured; Cricetinae; Curcumin; Cytoplasm; Models, Biological; Nanotechnology; Neuroprotective Agents; Peptide Fragments; Surface Plasmon Resonance

Curcumin is a natural polyphenol with evidence of antioxidant, anti-inflammatory and neuroprotective properties. Recent evidence also suggests that curcumin increases cognitive performance in animal models of dementia, and this effect would be related to its capacity to enhance adult neurogenesis. The aim of this study was to test the hypothesis that curcumin treatment would be able to preserve cognition by increasing neurogenesis and decreasing neuroinflammation in the model of dementia of Alzheimer's type induced by an intracerebroventricular injection of streptozotocin (ICV-STZ) in Wistar rats. The animals were injected with ICV-STZ or vehicle and curcumin treatments (25, 50 and 100mg/kg, gavage) were performed for 30days. Four weeks after surgery, STZ-lesioned animals exhibited impairments in short-term spatial memory (Object Location Test (OLT) and Y maze) and short-term recognition memory (Object Recognition Test - ORT), decreased cell proliferation and immature neurons (Ki-67- and doublecortin-positive cells, respectively) in the subventricular zone (SVZ) and dentate gyrus (DG) of hippocampus, and increased immunoreactivity for the glial markers GFAP and Iba-1 (neuroinflammation). Curcumin treatment in the doses of 50 and 100mg/kg prevented the deficits in recognition memory in the ORT, but not in spatial memory in the OLT and Y maze. Curcumin treatment exerted only slight improvements in neuroinflammation, resulting in no improvements in hippocampal and subventricular neurogenesis. These results suggest a positive effect of curcumin in object recognition memory which was not related to hippocampal neurogenesis.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Brain; Cognition; Curcumin; Dementia; Dentate Gyrus; Disease Models, Animal; Doublecortin Protein; Hippocampus; Male; Maze Learning; Memory, Short-Term; Neurogenesis; Neuroimmunomodulation; Neuroprotective Agents; Rats; Rats, Wistar; Spatial Memory

Detection of β-amyloid (Aβ) plaques in the brain is a very promising biomarker approach for early diagnosis of Alzheimer's disease (AD).. A series of curcumin analogs (1,5-diphenyl-1,4-pentadien-3-one derivatives) were synthesized and evaluated. Specific binding to Aβ plaques was demonstrated in vitro using postmortem AD homogenates, and the fluorescent staining and autoradiography in vitro of postmortem AD brain sections were performed.. Some compounds showed high binding affinities with Aβ plaques. Fluorescent staining indicated that compound 4e clearly stained Aβ plaques within AD brain sections. In biodistribution, radioiodinated ligand [. The results strongly suggested that [

Topics: Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Animals; Autoradiography; Brain; Curcumin; Female; Humans; Iodine Radioisotopes; Ligands; Male; Mice; Mice, Inbred ICR; Microscopy, Fluorescence; Protein Binding; Radiopharmaceuticals; Tissue Distribution

Several studies have indicated that neuroinflammation is indeed associated with neurodegenerative disease pathology. However, failures of recent clinical trials of anti-inflammatory agents in neurodegenerative disorders have emphasized the need to better understand the complexity of the neuroinflammatory process in order to unravel its link with neurodegeneration. Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer's disease (AD). Recent studies show an association between p25/Cdk5 hyperactivation and robust neuroinflammation. In addition, we recently reported the novel link between the p25/Cdk5 hyperactivation-induced inflammatory responses and neurodegenerative changes using a transgenic mouse that overexpresses p25 (p25Tg). In this study, we aimed to understand the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on p25-mediated neuroinflammation and the progression of neurodegeneration in p25Tg mice. The results from this study showed that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice. Moreover, this curcumin-mediated suppression of neuroinflammation reduced the progression of p25-induced tau/amyloid pathology and in turn ameliorated the p25-induced cognitive impairments. It is widely acknowledged that to treat AD, one must target the early-stage of pathological changes to protect neurons from irreversible damage. In line with this, our results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, our data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents; Astrocytes; Brain; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Curcumin; Humans; Inflammation; Memory Disorders; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Nerve Degeneration; Neuroimmunomodulation; Neuroprotective Agents; Nootropic Agents

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder that has a progression that is closely associated with oxidative stress. It has long been speculated that the reactive oxygen species (ROS) level in AD brains is much higher than that in healthy brains. However, evidence from living beings is scarce. Inspired by the "chemistry of glow stick," we designed a near-IR fluorescence (NIRF) imaging probe, termed CRANAD-61, for sensing ROS to provide evidence at micro- and macrolevels. In CRANAD-61, an oxalate moiety was utilized to react with ROS and to consequentially produce wavelength shifting. Our in vitro data showed that CRANAD-61 was highly sensitive and rapidly responsive to various ROS. On reacting with ROS, its excitation and emission wavelengths significantly shifted to short wavelengths, and this shifting could be harnessed for dual-color two-photon imaging and transformative NIRF imaging. In this report, we showed that CRANAD-61 could be used to identify "active" amyloid beta (Aβ) plaques and cerebral amyloid angiopathy (CAA) surrounded by high ROS levels with two-photon imaging (microlevel) and to provide relative total ROS concentrations in AD brains via whole-brain NIRF imaging (macrolevel). Lastly, we showed that age-related increases in ROS levels in AD brains could be monitored with our NIRF imaging method. We believe that our imaging with CRANAD-61 could provide evidence of ROS at micro- and macrolevels and could be used for monitoring ROS changes under various AD pathological conditions and during drug treatment.

Topics: Alzheimer Disease; Animals; Brain; Curcumin; Disease Models, Animal; Female; Humans; Mice; Mice, Transgenic; Microscopy, Fluorescence, Multiphoton; Molecular Imaging; Molecular Probes; Oxalates; Oxidative Stress; Photons; Plaque, Amyloid; Reactive Oxygen Species; Sensitivity and Specificity; Spectroscopy, Near-Infrared

Caveolin-1, the marker protein of membranal caveolae, is not only involved in cholesterol regulation, but also participates in the cleavage of amyloid [Formula: see text]-protein precursor (APP) and the generation of [Formula: see text]-amyloid peptide. It has been reported to be tightly related with Tau. In our previous studies, curcumin has been confirmed to play a neuroprotective role in Alzheimer's disease (AD), but its effects on Caveolin-1, Tau and their correlation, and the mechanism is still unknown. As such, in the present study, N2a/WT cells, N2a/APP695swe cell and six-month-old APP/PS1 double transgenic mice were enrolled. After curcumin treatment, the expression of Caveolin-1, Tau and their relationship was detected, and the potential mechanisms were explored. The results showed that in the N2a/APP695swe cells, curcumin not only decreased the number of caveolae, but also made their membrane to be thinner; and curcumin could decreased the expression of phosphorylated Tau (P-Tau(ser404)/Tau) and Caveolin-1 ([Formula: see text]), but the expression of phosphorylated GSK-3[Formula: see text] (P-GSK-3[Formula: see text]/GSK-3[Formula: see text] was increased ([Formula: see text]). In APP/PS1 transgenic mice, the same results were observed. Taken together, our data suggest that curcumin may play an important role in AD via reducing Caveolin-1, inactivating GSK-3[Formula: see text] and inhibiting the abnormal excessive phosphorylation of Tau, which will provide a new theory for AD treatment with curcumin.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Caveolae; Caveolin 1; Cells, Cultured; Curcumin; Down-Regulation; Gene Expression; Glycogen Synthase Kinase 3; Mice, Transgenic; Molecular Targeted Therapy; Phosphorylation; Phytotherapy; tau Proteins

Alzheimer's disease is a progressive neurodegenerative disease characterized by loss of hippocampal neurons leading to memory deficits and cognitive decline. Studies suggest that levels of the vasoactive peptide endothelin-1 (ET-1) are increased in the brain tissue of Alzheimer's patients. Curcumin, the main ingredient of the spice turmeric, has been shown to have anti-inflammatory, anti-cancer, and neuroprotective effects. However, the mechanisms underlying some of these beneficial effects are not completely understood. The objective of this study was to determine if curcumin could protect hippocampal neurons from ET-1 mediated cell death and examine the involvement of c-Jun in this pathway.. Primary hippocampal neurons from rat pups were isolated using a previously published protocol. Viability of the cells was measured by the live/dead assay. Immunoblot and immunohistochemical analyses were performed to analyze c-Jun levels in hippocampal neurons treated with either ET-1 or a combination of ET-1 and curcumin. Apoptotic changes were evaluated by immunoblot detection of cleaved caspase-3, cleaved fodrin, and a caspase 3/7 activation assay.. ET-1 treatment produced a 2-fold increase in the levels of c-Jun as determined by an immunoblot analysis in hippocampal neurons. Co-treatment with curcumin significantly attenuated the ET-1 mediated increase in c-Jun levels. ET-1 caused increased neuronal cell death of hippocampal neurons indicated by elevation of cleaved caspase-3, cleaved fodrin and an increased activity of caspases 3 and 7 which was attenuated by co-treatment with curcumin. Blockade of JNK, an upstream effector of c-Jun by specific inhibitor SP600125 did not fully protect from ET-1 mediated activation of pro-apoptotic enzymes in primary hippocampal cells.. Our data suggests that one mechanism by which curcumin protects against ET-1-mediated cell death is through blocking an increase in c-Jun levels. Other possible mechanisms include decreasing pro-apoptotic signaling activated by ET-1 in primary hippocampal neurons.

Topics: Alzheimer Disease; Animals; Apoptosis; Carrier Proteins; Caspase 3; Caspase 7; Cell Death; Cells, Cultured; Curcumin; Endothelin-1; Hippocampus; Microfilament Proteins; Neurons; Neuroprotective Agents; Proto-Oncogene Proteins c-jun; Rats; Rats, Sprague-Dawley; Signal Transduction

Curcumin and its derivatives have attracted great interest in the prevention and treatment of Alzheimer's disease, thanks both to the ability to hinder the formation of amyloid-beta (Aβ) aggregates and the ability to bind Cu (II) ion. In this article, we explore the ability of curcumin derivatives of K2T series to affect amyloid Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Coordination Complexes; Copper; Curcumin; DNA; Drug Evaluation, Preclinical; Free Radical Scavengers; Humans; Inhibitory Concentration 50; Microscopy, Atomic Force; Molecular Structure; Peptide Fragments; Structure-Activity Relationship

We report a novel approach for the delivery of curcumin to the brain via inhalation of the aerosol for the potential treatment of Alzheimer's disease. The percentage of plaque fraction in the subiculum and hippocampus reduced significantly when young 5XFAD mice were treated with inhalable curcumin over an extended period of time compared to age-matched nontreated counterparts. Further, treated animals demonstrated remarkably improved overall cognitive function, no registered systemic or pulmonary toxicity associated with inhalable curcumin observed during the course of this work.

Topics: Administration, Inhalation; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cognition Disorders; Curcumin; Dendritic Spines; Disease Models, Animal; Hippocampus; Humans; Maze Learning; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron, Transmission; Mutation; Neurons; Presenilin-1

We present a reconstituted lipoprotein-based nanoparticle platform comprising a curcumin fluorescent motif and an NIR responsive gold core. This multifunctional nanosystem is successfully used for aggregation-dependent fluorescence detection and photothermal disassembly of insoluble amyloid aggregates.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Curcumin; Fluorescent Dyes; Gold; Humans; Infrared Rays; Light; Lipoproteins; Nanoparticles; Peptide Fragments; Protein Aggregates; Spectrometry, Fluorescence; Temperature

Recent studies have shown the therapeutic potential of curcumin in Alzheimer's disease (AD). In 2014, our lab found that curcumin reduced Aβ40, Aβ42 and Aβ-derived diffusible ligands in the mouse hippocampus, and improved learning and memory. However, the mechanisms underlying this biological effect are only partially known. There is considerable evidence in brain metabolism studies indicating that AD might be a brain-specific type of diabetes with progressive impairment of glucose utilisation and insulin signalling. We hypothesised that curcumin might target both the glucose metabolism and insulin signalling pathways. In this study, we monitored brain glucose metabolism in living APPswe/PS1dE9 double transgenic mice using a micro-positron emission tomography (PET) technique. The study showed an improvement in cerebral glucose uptake in AD mice. For a more in-depth study, we used immunohistochemical (IHC) staining and western blot techniques to examine key factors in both glucose metabolism and brain insulin signalling pathways. The results showed that curcumin ameliorated the defective insulin signalling pathway by upregulating insulin-like growth factor (IGF)-1R, IRS-2, PI3K, p-PI3K, Akt and p-Akt protein expression while downregulating IR and IRS-1. Our study found that curcumin improved spatial learning and memory, at least in part, by increasing glucose metabolism and ameliorating the impaired insulin signalling pathways in the brain.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Curcumin; Glucose; Insulin; Insulin Receptor Substrate Proteins; Memory; Mice, Inbred C57BL; Mice, Transgenic; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Somatomedin; Signal Transduction; Spatial Learning

Multifunctional LUV liposomes (mf-LIPs) were developed, having a curcumin-lipid ligand (TREG) with affinity towards amyloid species, together with ligands to target the transferrin and the LDL receptors of the blood-brain-barrier (BBB), on their surface. mf-LIPs were evaluated for their brain targeting, on hCMEC/D3 monolayers, and for their ability to inhibit Aβ-peptide aggregation. The transport of mf-LIP across hCMEC/D3 monolayers was similar to that of BBB-LIPs, indicating that the presence of TREG on their surface does not reduce their brain targeting potential. Likewise, mf-LIP inhibitory effect on Aβ aggregation was similar to that of LIPs functionalized only with TREG, proving that the presence of brain targeting ligands does not reduce the functionality of the amyloid-specific ligand. Addition of the curcumin-lipid in some liposome types was found to enhance their integrity and reduce the effect of serum proteins on their interaction with brain endothelial cells. Finally, preliminary in vivo results confirm the in vitro findings. Concluding, the current results reveal the potential of the specific curcumin-lipid derivative as a component of multifunctional LIPs with efficient brain targeting capability, intended to act as a theragnostic system for AD.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Biological Transport; Blood-Brain Barrier; Brain; Cells, Cultured; Curcumin; Endothelial Cells; Humans; Liposomes; Transferrin

Curcumin (CRM) and nerve growth factor (NGF) were entrapped in liposomes (LIP) with surface wheat germ agglutinin (WGA) to downregulate the phosphorylation of kinases in Alzheimer's disease (AD) therapy. Cardiolipin (CL)-conjugated LIP carrying CRM (CRM-CL/LIP) and also carrying NGF (NGF-CL/LIP) were used with AD models of SK-N-MC cells and Wistar rats after an insult with β-amyloid peptide (Aβ). We found that CRM-CL/LIP inhibited the expression of phosphorylated p38 (p-p38), phosphorylated c-Jun N-terminal kinase (p-JNK), and p-tau protein at serine 202 and prevented neurodegeneration of SK-N-MC cells. In addition, NGF-CL/LIP could enhance the quantities of p-neurotrophic tyrosine kinase receptor type 1 and p-extracellular signal-regulated kinase 5 for neuronal rescue. Moreover, WGA-grafted CRM-CL/LIP and WGA-grafted NGF-CL/LIP significantly improved the permeation of CRM and NGF across the blood-brain barrier, reduced Aβ plaque deposition and the malondialdehyde level, and increased the percentage of normal neurons and cholinergic activity in the hippocampus of AD rats. Based on the marker expressions and in vivo evidence, current LIP carriers can be promising drug delivery systems to protect nervous tissue against Aβ-induced apoptosis in the brain during the clinical management of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cardiolipins; Cell Survival; Curcumin; Drug Delivery Systems; Fluorescence; Hippocampus; Humans; Immunohistochemistry; JNK Mitogen-Activated Protein Kinases; Kinetics; Liposomes; Male; Nerve Degeneration; Neurons; Particle Size; Phosphorylation; Rats, Wistar; Static Electricity; tau Proteins; Wheat Germ Agglutinins

Antioxidant, anticholinesterase and antidiabetic activities of three curcuminoids isolated from the Curcuma longa were simultaneously tested and compared in this study. The highest antioxidant power was detected for curcumin with the applied methods. The drug potentials of curcuminoids for Alzheimer's disease were controlled. Bisdemethoxycurcumin (BDMC) showed substantial inhibitory activity. The activity of demethoxycurcumin (DMC) followed BDMC, whereas curcumin showed very little acetylcholinesterase inhibition activity. Antidiabetic activity of curcuminoids was evaluated by their α-glucosidase inhibitory activities. All curcuminoids show activities with decreasing order as BDMC > curcumin > DMC. The significant activities of BDMC compared to its isomers and examination of chemical structures of isomers might be a starting point in designing new drugs for Alzheimer's and Diabetes Mellitus.

Topics: Alzheimer Disease; Antioxidants; Cholinesterase Inhibitors; Curcuma; Curcumin; Diarylheptanoids; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Plant Extracts

A novel series of thiazole acetamides was synthesized in excellent yields and characterized with the aid of various spectroscopic and elemental analysis. These compounds were evaluated for in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities for possible benefit in Alzheimers disease (AD). Among the synthesized compound, 6d was identified as the most potent compound of AChE (IC50=3.14±0.16 μM) with a selectivity index (SI) of 2.94 against BuChE. These compounds were further tested for inhibition of Aβ aggregation and β-secretase, where it showed potent inhibition which confirmed its multifactorial benefits in AD. The toxicity and docking study were also carried out to exemplify the pharmacological profile of compound 6d as prospective lead molecule against AD.

Topics: Acetamides; Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Binding Sites; Butyrylcholinesterase; Cell Survival; Cholinesterase Inhibitors; Drug Design; Drug Evaluation, Preclinical; HeLa Cells; Humans; Inhibitory Concentration 50; Molecular Docking Simulation; Protein Binding; Protein Structure, Tertiary; Structure-Activity Relationship; Thiazoles

A series of pterostilbene-O-acetamidoalkylbenzylamines were designed, synthesized and evaluated as dual inhibitors of AChE and BuChE. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and inhibitory effects on self-induced Aβ1-42 aggregation and HuAChE-induced Aβ1-40 aggregation were also tested. The results showed that most of these compounds could effectively inhibit AChE and BuChE. Particularly, compound 21d exhibited the best AChE inhibitory activity (IC50=0.06 μM) and good inhibition of BuChE (IC50=28.04 μM). Both the inhibition kinetic analysis and molecular modeling study revealed that these compounds showed mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activity. However, the inhibitory activities against self-induced and HuAChE-induced Aβ aggregation of these new derivatives were unsatisfied. Taking into account the results of the biological evaluation, further modifications will be designed in order to increase the potency on the different targets. The results displayed in this Letter can be a new starting point for further development of multifunctional agents for Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Benzylamines; Butyrylcholinesterase; Cholinesterase Inhibitors; Cholinesterases; Dose-Response Relationship, Drug; Humans; Molecular Structure; Peptide Fragments; Protein Aggregates; Protein Aggregation, Pathological; Stilbenes; Structure-Activity Relationship

This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrrolizinones as potential antioxidant, metal chelating or amyloid β (βA) aggregation inhibitors. Some derivatives exhibited interesting results in regard to several of the performed evaluations and appear as valuable Multi-Target Directed Ligands with potential therapeutic interest in Alzheimer's disease. Among them, compound 29 particularly appears as a valuable radical and NO scavenger, a Cu(II) and Fe(II) chelating agent and exhibits moderate βA aggregation inhibition properties. These activities, associated to a good predictive bioavailability and a lack of cytotoxicity, design it as a promising hit for further in vivo investigation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Benzyl Compounds; Cell Proliferation; Dose-Response Relationship, Drug; Humans; KB Cells; Models, Molecular; Molecular Structure; Protein Aggregates; Protein Binding; Pyrroles; Structure-Activity Relationship; Tumor Cells, Cultured

A novel series of ferulic acid-memoquin hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro studies showed that most of the compounds exhibited a significant ability to inhibit acetylcholinesterase (AChE) (IC50 of 3.2-34.7μM) and self-induced β-amyloid (Aβ1-42) aggregation (30.8-39.1%, 25μM), to act as potential antioxidants (ORAC-FL value of 0.9-1.3). In particular, compound 17d had the greatest ability to inhibit AChE (IC50=3.2μM), and Aβ1-42 aggregation (30.8%) was also an excellent antioxidant and neuroprotectant. Moreover, it is capable of disaggregating self-induced Aβ aggregation. Furthermore, 17d could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 17d is a potential multifunctional agent for the treatment of AD.

Topics: Alkanes; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Chemistry Techniques, Synthetic; Cholinesterase Inhibitors; Coumaric Acids; Drug Design; Drug Evaluation, Preclinical; Ethylamines; Humans; Hydrogen Peroxide; Neuroprotective Agents; PC12 Cells; Rats

A series of 4-hydroxyl aurone derivatives were designed synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The results demonstrated that most of the derivatives exhibited good multifunctional properties. Among them, compound 14e displayed good inhibitory activities of self- and Cu(2+)-induced Aβ1-42 aggregation with 99.2% and 84.0% at 25μM, respectively, and high antioxidant activity with a value 1.90-fold of Trolox. In addition, 14e also showed remarkable inhibitory activities of both monoamine oxidase A and B with IC50 values of 0.271μM and 0.393μM, respectively. However the 6-methoxyl aurones 15a-c revealed excellent selectivity toward MAO-B. Furthermore, the representative compounds 14e and 15b displayed good metal-chelating abilities and blood-brain barrier (BBB) permeabilities in vitro.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Benzofurans; Blood-Brain Barrier; Chelating Agents; Copper; Humans; Models, Molecular; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Peptide Fragments; Protein Aggregates; Swine

A series of new cyanopyridine-triazine hybrids were designed, synthesized and screened as multitargeted anti-Alzheimer's agents. These molecules were designed while using computational techniques and were synthesized via a feasible concurrent synthetic route. Inhibition potencies of synthetic compounds 4a-4h against cholinesterases, Aβ1-42 disaggregation, oxidative stress, cytotoxicity, and neuroprotection against Aβ1-42-induced toxicity of the synthesized compounds were evaluated. Compounds 4d and 4h showed promising inhibitory activity on acetylcholinesterase (AChE) with IC50 values 0.059 and 0.080μM, respectively, along with good inhibition selectivity against AChE over butyrylcholinesterase (BuChE). Molecular modelling studies revealed that these compounds interacted simultaneously with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The mixed type inhibition of compound 4d further confirmed their dual binding nature in kinetic studies. Furthermore, the results from neuroprotection studies of most potent compounds 4d and 4h indicate that these derivatives can reduce neuronal death induced by H2O2-mediated oxidative stress and Aβ1-42 induced cytotoxicity. In addition, in silico analysis of absorption, distribution, metabolism and excretion (ADME) profile of best compounds 4d and 4h revealed that they have drug like properties. Overall, these cyanopyridine-triazine hybrids can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Butyrylcholinesterase; Cell Line; Cholinesterase Inhibitors; Drug Design; Humans; Molecular Docking Simulation; Molecular Targeted Therapy; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Pyridines; Triazines

In present study a series of triazolopyrimidine-quinoline and cyanopyridine-quinoline hybrids were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs). Molecular docking and scoring was utilized for the design of inhibitors. The molecules were synthesized via an easily accessible, convergent synthetic route. Three triazolopyrimidine based compounds showed nanomolar activity towards acetylcholinesterase. Among them, Ethyl 6-fluoro-4-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)quinoline-3-carboxylate (10d), strongly inhibited AChE with IC50 value of 42 nM. Furthermore compound 10d was identified as most promising compound with 12 fold selectivity against butyrylcholinesterase (BuChE). This compound displayed a composed multitargeted profile with promising inhibition of self-induced and AChE - induced Aβ aggregation and antioxidant activity.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Butyrylcholinesterase; Cell Line, Tumor; Cell Survival; Chemistry Techniques, Synthetic; Cholinesterase Inhibitors; Drug Evaluation, Preclinical; Humans; Kinetics; Molecular Docking Simulation; Peptide Fragments; Protein Aggregates; Protein Conformation; Pyrimidines

A new series of 4-dimethylamine flavonoid derivatives were designed and synthesized as potential multifunctional anti-Alzheimer agents. The inhibition of cholinesterase activity, self-induced β-amyloid (Aβ) aggregation, and antioxidant activity by these derivatives was investigated. Most of the compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. A Lineweaver-Burk plot and molecular modeling study showed that these compounds targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. The derivatives showed potent self-induced Aβ aggregation inhibition and peroxyl radical absorbance activity. Moreover, compound 6d significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Thus, these compounds could become multifunctional agents for further development for the treatment of AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Cell Death; Chemistry Techniques, Synthetic; Cholinesterase Inhibitors; Dimethylamines; Drug Design; Flavonoids; Humans; Hydrogen Peroxide; Intracellular Space; Kinetics; Molecular Docking Simulation; PC12 Cells; Peptide Fragments; Protein Aggregates; Protein Conformation; Rats; Structure-Activity Relationship

A series of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)-1H-indene-1,3(2H)-diones were designed, synthesized and appraised as multifunctional anti-Alzheimer agents. In vitro studies of compounds 27-38 showed that these compounds exhibit moderate to excellent AChE, BuChE and Aβ aggregation inhibitory activity. Notably, compounds 34 and 38 appeared as most active multifunctional agents in the entire series and exhibited excellent inhibition against AChE (IC50=0.048μM: 34; 0.036μM: 38), Aβ aggregation (max% inhibition 82.2%, IC50=9.2μM: 34; max% inhibition 80.9%, IC50=10.11μM: 38) and displayed significant antioxidant potential in ORAC-FL assay. Both compounds also successfully diminished H2O2 induced oxidative stress in SH-SY5Y cells. Fascinatingly, compounds 34 and 38 showed admirable neuroprotective effects against H2O2 and Aβ induced toxicity in SH-SY5Y cells. Additionally, both derivatives showed no considerable toxicity in neuronal cell viability assay and represented drug likeness properties in the primarily pharmacokinetics study. All these results together, propelled out that compounds 34 and 38 might serve as promising multi-functional lead candidates for treatment of AD in the future.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Cell Line; Cholinesterase Inhibitors; Drug Design; Drug Evaluation, Preclinical; Humans; Hydrogen Peroxide; Indans; Kinetics; Microscopy, Electron, Transmission; Neuroprotective Agents

A novel series of compounds obtained by fusing the acetylcholinesterase (AChE) inhibitor donepezil and the antioxidant melatonin were designed as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (eqBuChE and hBuChE), and β-amyloid (Aβ) aggregation, and to act as potential antioxidants and biometal chelators. Especially, 4u displayed a good inhibition of AChE (IC50 value of 193nM for eeAChE and 273nM for hAChE), strong inhibition of BuChE (IC50 value of 73nM for eqBuChE and 56nM for hBuChE), moderate inhibition of Aβ aggregation (56.3% at 20μM) and good antioxidant activity (3.28trolox equivalent by ORAC assay). Molecular modeling studies in combination with kinetic analysis revealed that 4u was a mixed-type inhibitor, binding simultaneously to catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4u could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Taken together, these results strongly indicated the hybridization approach is an efficient strategy to identify novel scaffolds with desired bioactivities, and further optimization of 4u may be helpful to develop more potent lead compound for AD treatment.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Butyrylcholinesterase; Catalytic Domain; Cell Line, Tumor; Chelating Agents; Cholinesterase Inhibitors; Donepezil; Electrophorus; Horses; Humans; Indans; Indoles; Iron; Kinetics; Melatonin; Molecular Docking Simulation; Peptide Fragments; Piperidines; Protein Multimerization; Rats; Zinc

A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC50 values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, Aβ interaction, blood-brain barrier penetration (PAMPA-BBB+) and ADMET properties (in silico). Among them, 5c demonstrated excellent AChE inhibition (IC50: 85 nM for eeAChE, 73 nM for hAChE), metal chelation, and inhibitory effects on self-induced, hAChE-induced and Cu(2+)-induced Aβ1-42 aggregation (18.5%, 72.4% and 46.3%, at 20 μM). Kinetic analysis and molecular modeling studies suggested that 5c could bind simultaneously to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. More importantly, 5c exhibited significant neuroprotective potency against Aβ1-42-induced PC12 cell injury. Furthermore, the step-through passive avoidance test showed 5c significantly reversed scopolamine-induced memory deficit and no hepatotoxicity in mice. These results indicated that 5c might be a promising drug candidate for AD therapy.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Cell Survival; Cholinesterase Inhibitors; Copper; Donepezil; Drug Design; Humans; Indans; Kinetics; Liver; Mice; Models, Molecular; Peptide Fragments; Piperidines; Protein Aggregates; Protein Conformation

A series of 8- and 11-substituted oxoisoaporphine derivatives have been designed, synthesized, and tested for their ability to inhibit cholinesterase (ChE) in vitro and in vivo, and self-induced β-amyloid (Aβ) aggregation. Their autophagy activity and blood-brain barrier (BBB) permeability were also assessed. The new derivatives exhibited high AChE inhibitory activity in vivo and in intro. Over half the derivatives exhibited a significant in vitro inhibitory activity toward the self-induced Aβ aggregation. While, treatment of SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw) with derivatives was associated with significant reduction of Aβ secretion levels. Moreover, one-third of the synthetic compounds were predicted to be able to cross the BBB to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. Compounds 5b and 6b were chosen for assessing their autophagy activity. The fluorescence intensity of the BC12921 was decreased significantly after treatment with compounds. The result encourages us to study such compounds thoroughly and systematically.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Aporphines; Autophagy; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Molecular Structure; Protein Aggregates; Structure-Activity Relationship; Tumor Cells, Cultured

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Humans; Middle Aged; Treatment Outcome

Neurological diseases such as Alzheimer's and Parkinson's diseases are incurable progressive neurological disorders caused by the degeneration of neuronal cells and characterized by motor and non-motor symptoms. Curcumin, a turmeric product, is an anti-inflammatory agent and an effective reactive oxygen and nitrogen species scavenging molecule. Hydrogen peroxide (H2O2) is the main source of oxidative stress, which is claimed to be the major source of neurological disorders. Hence, in this study we aimed to investigate the effect of curcumin on Ca(2+) signaling, oxidative stress parameters, mitochondrial depolarization levels and caspase-3 and -9 activities that are induced by the H2O2 model of oxidative stress in SH-SY5Y neuronal cells. SH-SY5Y neuronal cells were divided into four groups namely, the control, curcumin, H2O2, and curcumin + H2O2 groups. The dose and duration of curcumin and H2O2 were determined from published data. The cells in the curcumin, H2O2, and curcumin + H2O2 groups were incubated for 24 h with 5 µM curcumin and 100 µM H2O2. Lipid peroxidation and cytosolic free Ca(2+) concentrations were higher in the H2O2 group than in the control group; however, their levels were lower in the curcumin and curcumin + H2O2 groups than in the H2O2 group alone. Reduced glutathione (GSH) and glutathione peroxidase (GSH-Px) values were lower in the H2O2 group although they were higher in the curcumin and curcumin + H2O2 groups than in the H2O2 group. Caspase-3 activity was lower in the curcumin group than in the H2O2 group. In conclusion, curcumin strongly induced modulator effects on oxidative stress, intracellular Ca(2+) levels, and the caspase-3 and -9 values in an experimental oxidative stress model in SH-SY5Y cells.

Topics: Alzheimer Disease; Apoptosis; Calcium; Caspase 3; Cell Polarity; Cell Survival; Curcumin; Humans; Hydrogen Peroxide; Mitochondria; Neurons; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species; Supranuclear Palsy, Progressive

Erythropoietin and curcumin showed promising neuroprotective effects in various models of Alzheimer's dementia. This study was designed to compare the beneficial effects of erythropoietin and/or curcumin in intracerebro-ventricular (ICV) streptozotocin-induced Alzheimer's like disease in rats. Rats received ICV injection of either saline (control, n=8 rats), or streptozotocin. Three weeks following surgery, streptozotocin-injected rats were assigned into 4 groups (8 rats each); vehicle, curcumin (80mg/kg/day, orally), erythropoietin (500 IU/kg every other day, intraperitoneally) and combined (curcumin and erythropoietin)-treated groups. After 3 months of treatment, rats were subjected to neurobehavioral testing, and then killed for biochemical and histological assessment of hippocampus. Fas ligand protein and caspase-8 activity as mediators of extrinsic apoptotic pathway, oxidative stress markers (malondialdehyde and reduced glutathione) and β-amyloid (1-40 and 1-42) peptides were measured. The results showed that administration of erythropoietin suppressed extrinsic apoptosis better than curcumin, while curcumin was more effective in combating oxidative stress in ICV-streptozotocin injected rats. Both erythropoietin and curcumin treatments (individually or combined) equally reduced the hippocampal β-amyloid accumulation and improved cognitive impairment in Morris water maze and passive avoidance tasks. The combined treatment was the most effective in ameliorating apoptosis and oxidative stress rather than behavioral responses or β-amyloid burden. In conclusion, ICV-streptozotocin-induced Alzheimer's dementia activates hippocampal Fas ligand-mediated apoptosis, which could be reduced by erythropoietin and/or curcumin treatment. Curcumin supplementation alone could ameliorate cognitive deficits and reverse biochemical alterations in ICV-streptozotocin Alzheimer's rat model without the hazardous polycythemic effect of long-term erythropoietin injection.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Apoptosis; Behavior, Animal; Curcumin; Erythropoietin; Hematocrit; Hippocampus; Male; Oxidative Stress; Rats; Rats, Wistar; Retention, Psychology; Signal Transduction; Spatial Learning; Streptozocin

Various food constituents have been proposed as disease-modifying agents for Alzheimer's disease (AD), due to epidemiological evidence of their beneficial effects, and for their ability to ameliorate factors linked to AD pathogenesis, namely by: chelating iron, copper and zinc; scavenging reactive oxygen species; and suppressing the fibrillation of amyloid-beta peptide (Aβ). In this study, nine different food constituents (l-ascorbic acid, caffeic acid, caffeine, curcumin, (-)-epigallocatechin gallate (EGCG), gallic acid, propyl gallate, resveratrol, and α-tocopherol) were investigated for their effects on the above factors, using metal chelation assays, antioxidant assays, and assays of Aβ42 fibrillation. An assay method was developed using 5-Br-PAPS to examine the complexation of Zn(II) and Cu(II). EGCG, gallic acid, and curcumin were identified as a multifunctional compounds, however their poor brain uptake might limit their therapeutic effects. The antioxidants l-ascorbic acid and α-tocopherol, with better brain uptake, deserve further investigation for specifically addressing oxidative stress within the AD brain.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Catechin; Chelating Agents; Curcumin; Free Radical Scavengers; Gallic Acid; Humans; Metals; Peptide Fragments

Curcumin is a natural product with multiple biological activities and numerous potential therapeutic applications. However, its poor systemic bioavailability fails to explain the potent pharmacological effects and hinders its clinical application. Using experimental and theoretical approaches, we compared curcumin and its degradation products for its biological activities against Alzheimer's disease (AD), including the superoxide anion radical (O2(.-))-scavenging activity, Aβ fibrils (fAβ) formation-inhibiting activity, and enzymatic inhibition activity. We showed that compared to the parent compound curcumin, the degradation products mixture possessed higher O2(.-)-scavenging activity and stronger inhibition against fAβ formation. The docking simulations revealed that the bioactive degradation products should make important contribution to the experimentally observed enzymatic inhibition activities of curcumin. Given that curcumin is readily degraded under physiological condition, our findings strongly suggested that the degradation products should make important contribution to the diverse biological activities of curcumin. Our novel findings not only provide novel insights into the complex pharmacology of curcumin due to its poor bioavailability, but also open new avenues for developing therapeutic applications of this natural product.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Curcumin; Free Radical Scavengers; Humans; Models, Biological; Superoxides

Topics: Alzheimer Disease; Cell Line, Tumor; Cell Survival; Curcumin; Drug Carriers; Herbal Medicine; Humans; Medicine, Traditional; Nanoparticles; Nanotechnology; Plant Extracts

Significant losses of synapses have been demonstrated in studies of Alzheimer's disease (AD), but structural and functional changes in synapses that depend on alterations of the postsynaptic density (PSD) area occur prior to synaptic loss and play a crucial role in the pathology of AD. Evidence suggests that curcumin can ameliorate the learning and memory deficits of AD. To investigate the effects of curcumin on synapses, APPswe/PS1dE9 double transgenic mice (an AD model) were used, and the ultra-structures of synapses and synapse-associated proteins were observed. Six months after administration, few abnormal synapses were observed upon electron microscopy in the hippocampal CA1 areas of the APPswe/PS1dE9 double transgenic mice. The treatment of the mice with curcumin resulted in improvements in the quantity and structure of the synapses. Immunohistochemistry and western blot analyses revealed that the expressions of PSD95 and Shank1 were reduced in the hippocampal CA1 areas of the APPswe/PS1dE9 double transgenic mice, but curcumin treatment increased the expressions of these proteins. Our findings suggest that curcumin improved the structure and function of the synapses by regulating the synapse-related proteins PSD95 and Shank1.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Curcumin; Disease Models, Animal; Hippocampus; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Presenilin-1; Synapses

Gallium-68 is a positron-emitting isotope that can be used in positron-emission tomography imaging agents. Alzheimer's disease is associated with the formation of plaques in the brain primarily comprised of aggregates of a 42 amino acid protein called amyloid-β. With the goal of synthesising charge neutral, low molecular weight, lipophilic gallium complexes with the potential to cross the blood-brain barrier and bind to Aβ plaques we have used an ancillary tetradentate N

Topics: Alzheimer Disease; Autopsy; Brain; Coordination Complexes; Crystallography, X-Ray; Curcumin; Gallium; Humans; Immunohistochemistry; Plaque, Amyloid; Schiff Bases; Spectrometry, Fluorescence

We have recently developed a bivalent strategy to provide novel compounds that potentially target multiple risk factors involved in the development of Alzheimer's disease (AD). Our previous studies employing a bivalent compound with a shorter spacer (17MN) implicated that this compound can localize into mitochondria and endoplasmic reticulum (ER), thus interfering with the change of mitochondria membrane potential (MMP) and Ca(2+) levels in MC65 cells upon removal of tetracycline (TC). In this report, we examined the effects by a bivalent compound with a longer spacer (21MO) in MC65 cells. Our results demonstrated that 21MO suppressed the change of MMP, possibly via interaction with the mitochondrial complex I in MC65 cells. Interestingly, 21MO did not show any effects on the Ca(2+) level upon TC removal in MC65 cells. Our previous studies suggested that the mobilization of Ca(2+) in MC65 cells, upon withdraw of TC, originated from ER, so the results implicated that 21MO may preferentially interact with mitochondria in MC65 cells under the current experimental conditions. Collectively, the results suggest that bivalent compounds with varied spacer length and cell membrane anchor moiety may exhibit neuroprotective activities via different mechanisms of action.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Calcium; Cell Line; Cholesterol; Curcumin; Endoplasmic Reticulum; Humans; Membrane Potential, Mitochondrial; Mitochondria; Neurons; Neuroprotective Agents; Risk Factors

Epidemiological data imply links between the increasing incidences of Alzheimer's disease (AD) and type 2 diabetes mellitus. In this study, an AD rat model was established by combining treatments with intracerebroventricular streptozotocin (icv-STZ) and subcutaneous D-galactose, and the effects of curcumin on depressing AD-like symptoms were investigated. In the AD model group, rats were treated with icv-STZ in each hippocampus with 3.0 mg/kg of bodyweight once and then were subcutaneously injected with D-galactose daily (125 mg/kg of bodyweight) for 7 weeks. In the curcumin-protective group, after icv-STZ treatment, rats were treated with D-galactose (the same as in the AD model group) and intraperitoneally injected with curcumin daily (10 mg/kg of bodyweight) for 7 weeks. Vehicle-treated rats were treated as control. Compared with the vehicle control, the amount of protein carbonylation and glutathione in liver, as well as malondialdehyde in serum, were upregulated but glutathione peroxidase activity in blood was downregulated in the AD model group. The shuttle index and locomotor activity of rats in the AD model group were decreased compared with the vehicle control group. Furthermore, AD model rats showed neuronal damage and neuron loss with formation of amyloid-like substances and neurofibrillary tangles, and the levels of both β-cleavage of AβPP and phosphorylation of tau (Ser396) were significantly increased compared with the vehicle control group. Notably, compared with the AD model group, oxidative stress was decreased and the abilities of active avoidance and locomotor activity were improved, as well as attenuated neurodegeneration, in the curcumin-protective group. These results imply the applications of this animal model for AD research and of curcumin in the treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Curcumin; Disease Models, Animal; Galactose; Glutathione; Hippocampus; Injections, Intraventricular; Injections, Subcutaneous; Male; Malondialdehyde; Maze Learning; Neuroprotective Agents; Presenilin-1; Protein Carbonylation; Rats; Rats, Sprague-Dawley; Streptozocin; tau Proteins

Neurons die in Alzheimer's disease (AD) and are not effectively replaced. An alternative approach to maintain nerve cell number is to identify compounds that stimulate the proliferation of endogenous neural stem cells in old individuals to replace lost neurons. However, unless a neurogenic drug is also neuroprotective, the replacement of lost neurons will not be sufficient to stop disease progression.. The neuroprotective AD drug candidate J147 is shown to enhance memory, improve dendritic structure, and stimulate cell division in germinal regions of the brains of very old mice. Based on the potential neurogenic potential of J147, a neuronal stem cell screening assay was developed to optimize derivatives of J147 for human neurogenesis.. The best derivative of J147, CAD-031, maintains the neuroprotective and memory enhancing properties of J147, yet is more active in the human neural stem cell assays.. The combined properties of neuroprotection, neurogenesis, and memory enhancement in a single drug are more likely to be effective for the treatment of age-associated neurodegenerative disorders than any individual activity alone.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cell Differentiation; Cells, Cultured; Curcumin; Disease Models, Animal; Drug Discovery; Embryonic Stem Cells; Female; Fibroblast Growth Factor 2; Gene Expression Regulation; Humans; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Presenilin-1

Alzheimer's disease (AD) is the most common form of dementia caused by the formation of Aβ aggregates. So far, no effective medicine for the treatment of AD is available. Many efforts have been made to find effective medicine to cope with AD. Curcumin is a drug candidate for AD, being a potent anti-amyloidogenic compound, but the results of clinical trials for it were either negative or inclusive. In the present study, we took advantages from accumulated knowledge about curcumin and have screened out four compounds that have chemical and structural similarity with curcumin more than 80% from all FDA-approved oral drugs. Using all-atom molecular dynamics simulation and the free energy perturbation method we showed that among predicted compounds anti-arrhythmic medication propafenone shows the best anti-amyloidogenic activity. The in vitro experiment further revealed that it can inhibit Aβ aggregation and protect cells against Aβ induced cytotoxicity to almost the same extent as curcumin. Our results suggest that propafenone may be a potent drug for the treatment of Alzheimer's disease.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Anti-Arrhythmia Agents; Binding Sites; Biological Availability; Cell Survival; Computer Simulation; Curcumin; Dose-Response Relationship, Drug; Drug Interactions; Free Radicals; Hydrogen Bonding; Molecular Docking Simulation; Molecular Dynamics Simulation; Peptide Fragments; Propafenone; Protein Aggregates; Protein Structure, Secondary; Static Electricity; Thermodynamics

In the one-trial taste-avoidance task in day-old chicks, acetylcholine receptor activation has been shown to be important for memory formation. Injection of scopolamine produces amnesia, which appears to be very similar in type to that of Alzheimer's disease, which is correlated with low levels of acetylcholine in the brain. Traditional pharmacological treatments of Alzheimer's disease, such as cholinesterase inhibitors and glutamate receptor blockers, improve memory and delay the onset of impairments in memory compared with placebo controls. These agents also ameliorate scopolamine-induced amnesia in the day-old chick trained on the one-trial taste-avoidance task. The present experiments examined the ability of two less traditional treatments for Alzheimer's disease, phosphatidylserine and curcumin, to ameliorate scopolamine-induced amnesia in day-old chicks. The results showed that 37.9 mmol/l phosphatidylserine and 2.7 mmol/l curcumin significantly improved retention in chicks administered scopolamine, whereas lower doses were not effective. Scopolamine did not produce state-dependent learning, indicating that this paradigm in day-old chicks might be a useful one to study the effects of possible Alzheimer's treatments. In addition, chicks administered curcumin or phosphatidylserine showed little avoidance of a bead associated with water reward, indicating that these drugs did not produce response inhibition. The current results extend the findings that some nontraditional memory enhancers can ameliorate memory impairment and support the hypothesis that these treatments might be of benefit in the treatment of Alzheimer's disease.

Topics: Alzheimer Disease; Amnesia; Animals; Avoidance Learning; Chickens; Cholinergic Antagonists; Curcumin; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Male; Memory; Phosphatidylserines; Reward; Scopolamine

Deposition of amyloid beta protein (Aβ) is a key component in the pathogenesis of Alzheimer's disease (AD). As an anti-amyloid natural polyphenol, curcumin (Cur) has been used as a therapy for AD. Its fluorescent activity, preferential binding to Aβ, as well as structural similarities with other traditional amyloid-binding dyes, make it a promising candidate for labeling and imaging of Aβ plaques in vivo. The present study was designed to test whether dietary Cur and nanocurcumin (NC) provide more sensitivity for labeling and imaging of Aβ plaques in brain tissues from the 5×-familial AD (5×FAD) mice than the classical Aβ-binding dyes, such as Congo red and Thioflavin-S. These comparisons were made in postmortem brain tissues from the 5×FAD mice. We observed that Cur and NC labeled Aβ plaques to the same degree as Aβ-specific antibody and to a greater extent than those of the classical amyloid-binding dyes. Cur and NC also labeled Aβ plaques in 5×FAD brain tissues when injected intraperitoneally. Nanomolar concentrations of Cur or NC are sufficient for labeling and imaging of Aβ plaques in 5×FAD brain tissue. Cur and NC also labeled different types of Aβ plaques, including core, neuritic, diffuse, and burned-out, to a greater degree than other amyloid-binding dyes. Therefore, Cur and or NC can be used as an alternative to Aβ-specific antibody for labeling and imaging of Aβ plaques ex vivo and in vivo. It can provide an easy and inexpensive means of detecting Aβ-plaque load in postmortem brain tissue of animal models of AD after anti-amyloid therapy.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Coloring Agents; Curcumin; Diet; Disease Models, Animal; Mice; Mice, Transgenic; Molecular Structure; Nanostructures; Plaque, Amyloid; Solubility

Neprilysin (NEP) is the most important Aβ-degrading enzyme. Its expression level decreases with age and inversely correlated with amyloid accumulation, suggesting its correlation with the late-onset of Alzheimer's disease. Recently, many reports showed that upregulating NEP level is a promising strategy in the prevention and therapy of Alzheimer's disease. Here, we used a sensitive fluorescence-based Aβ digestion assay to screen 25 curcumin analogs for their ability to upregulate NEP activity. To our surprise, four compounds, dihydroxylated curcumin, monohydroxylated demethoxycurcumin, and mono- and di-hydroxylated bisdemethoxycurcumin, increased NEP activity, while curcumin did not. The ability of these polyhydroxycurcuminoids to upregulate NEP was further confirmed by mRNA and protein expression levels in the cell and mouse models. Finally, feeding monohydroxylated demethoxycurcumin (also named demethylcurcumin) or dihydroxylated bisdemethoxycurcumin (also named bisdemethylcurcumin) to APPswe/PS1dE9 double transgenic mice upregulated NEP levels in the brain and reduced Aβ accumulation in the hippocampus and cortex. These polyhydroxycurcuminoids offer hope in the prevention of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line, Tumor; Curcumin; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Neprilysin; Up-Regulation

The presence of β-amyloid (Aβ) containing plaques in the brain is a hallmark of Alzheimer's disease (AD) and serves as a biomarker for confirmation of diagnosis postmortem. Early diagnosis is of great importance for optimal treatment and for monitoring disease progression in the brain. Highly specific and sensitive biomarkers are thus greatly needed to assess therapeutic efficacy, not only clinically, but also in terms of clearance of histopathological lesions and decelerated neurodegeneration. The objective of the present study was to give more insight into the binding of curcumin analogues, curcuminoids, to Aβ containing plaques in postmortem tissue from AD patients. In vitro autoradiography was utilized to explore affinity and displacement of the curcuminoids; curcumin, demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC) and dimethoxycurcumin (DIMC). We found that BDMC had the highest affinity for Aβ containing plaques in cortical AD brain tissue in comparison to other curcuminoids. Subsequently, [(3)H]BDMC showed significantly higher specific binding in cortical AD brain tissue compared to control subjects. These findings suggest that curcumin analogues, especially BDMC, may serve as a potential radioligands for Aβ plaque neuroimaging.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aminopyridines; Amyloid beta-Peptides; Autoradiography; Benzothiazoles; Curcumin; Diarylheptanoids; Female; Humans; Inhibitory Concentration 50; Male; Temporal Lobe

Deficits in glucose, impaired insulin signalling and brain insulin resistance are common in the pathogenesis of Alzheimer's disease (AD); therefore, some scholars even called AD type 3 diabetes mellitus. Curcumin can reduce the amyloid pathology in AD. Moreover, it is a well-known fact that curcumin has anti-oxidant and anti-inflammatory properties. However, whether or not curcumin could regulate the insulin signal transduction pathway in AD remains unclear. In this study, we used APPswe/PS1dE9 double transgenic mice as the AD model to investigate the mechanisms and the effects of curcumin on AD. Immunohistochemical (IHC) staining and a western blot analysis were used to test the major proteins in the insulin signal transduction pathway. After the administration of curcumin for 6 months, the results showed that the expression of an insulin receptor (InR) and insulin receptor substrate (IRS)-1 decreased in the hippocampal CA1 area of the APPswe/PS1dE9 double transgenic mice, while the expression of phosphatidylinositol-3 kinase (PI3K), phosphorylated PI3K (p-PI3K), serine-threonine kinase (AKT) and phosphorylated AKT (p-AKT) increased. Among the curcumin groups, the medium-dose group was the most effective one. Thus, we believe that curcumin may be a potential therapeutic agent that can regulate the critical molecules in brain insulin signalling pathways. Furthermore, curcumin could be adopted as one of the AD treatments to improve a patient's learning and memory ability.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Curcumin; Disease Models, Animal; Hippocampus; Insulin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphatidylinositol 3-Kinases; Phosphorylation; Receptor, Insulin; Signal Transduction

The rate of reconfiguration-or intramolecular diffusion-of monomeric Alzheimer (Aβ) peptides is measured and, under conditions that aggregation is more likely, peptide diffusion slows down significantly, which allows bimolecular associations to be initiated. By using the method of Trp-Cys contact quenching, the rate of reconfiguration is observed to be about five times faster for Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Curcumin; Humans; Kinetics; Protein Aggregates; Thermodynamics

The purpose of our study was to investigate the protective effects of a natural product-'curcumin'- in Alzheimer's disease (AD)-like neurons. Although much research has been done in AD, very little has been reported on the effects of curcumin on mitochondrial biogenesis, dynamics, function and synaptic activities. Therefore, the present study investigated the protective effects against amyloid β (Aβ) induced mitochondrial and synaptic toxicities. Using human neuroblastoma (SHSY5Y) cells, curcumin and Aβ, we studied the protective effects of curcumin against Aβ. Further, we also studied preventive (curcumin+Aβ) and intervention (Aβ+curcumin) effects of curcumin against Aβ in SHSY5Y cells. Using real time RT-PCR, immunoblotting and immunofluorescence analysis, we measured mRNA and protein levels of mitochondrial dynamics, mitochondrial biogenesis and synaptic genes. We also assessed mitochondrial function by measuring hydrogen peroxide, lipid peroxidation, cytochrome oxidase activity and mitochondrial ATP. Cell viability was studied using the MTT assay. Aβ was found to impair mitochondrial dynamics, reduce mitochondrial biogenesis and decrease synaptic activity and mitochondrial function. In contrast, curcumin enhanced mitochondrial fusion activity and reduced fission machinery, and increased biogenesis and synaptic proteins. Mitochondrial function and cell viability were elevated in curcumin treated cells. Interestingly, curcumin pre- and post-treated cells incubated with Aβ showed reduced mitochondrial dysfunction, and maintained cell viability and mitochondrial dynamics, mitochondrial biogenesis and synaptic activity. Further, the protective effects of curcumin were stronger in pretreated SHSY5Y cells than in post-treated cells, indicating that curcumin works better in prevention than treatment in AD-like neurons. Our findings suggest that curcumin is a promising drug molecule to treat AD patients.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biological Products; Cell Line, Tumor; Curcumin; Gene Expression Regulation; Humans; Mitochondria; Mitochondrial Dynamics; Neuroprotective Agents; Organelle Biogenesis; RNA, Messenger; Synapses

A novel series of clioquinol-moracin hybrids were designed and synthesized by fusing the pharmacophores of clioquinol and moracin M, and their activities as multitarget-directed ligands against Alzheimer's disease were evaluated. Biological activity results demonstrated that these hybrids possessed significant inhibitory activities against phosphodiesterase 4D (PDE4D) and Aβ aggregation as well as remarkable antioxidant effects and excellent blood-brain barrier permeability. The optimal compound, 18d (WBQ5187), exhibited excellent PDE4D inhibitory potency (IC50 = 0.32 μM), significant antioxidant effects, appropriate biometal chelating functions, and interesting properties that modulated self- and metal-induced Aβ aggregation. Two-dimensional NMR studies revealed that 18d had significant interactions with Aβ1-42 at the R5, H6, H14, Q15, and F20 residues. Furthermore, this typical hybrid possessed preeminent neuroprotective effects against inflammation in microglial cells. Most importantly, oral administration of 18d·HCl demonstrated marked improvements in cognitive and spatial memory in a rat model of Alzheimer's disease and protected hippocampal neurons from necrosis.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Benzofurans; Clioquinol; Cognition; Cyclic Nucleotide Phosphodiesterases, Type 4; Inflammation; Ligands; Male; Memory; Models, Molecular; Neurons; Neuroprotective Agents; Phosphodiesterase 4 Inhibitors; Protein Aggregates; Rats; Rats, Wistar; Resorcinols

Recent evidence supports the amyloid cascade hypothesis that a pathological change of amyloid β (Aβ) in the brain is an initiating event in Alzheimer's disease (AD). Accordingly, modulating the abnormal Aβ aggregation is considered a potential therapeutic target in AD. Curcumin, a low-molecular-weight polyphenol derived from the well-known curry spice turmeric, has shown favorable effects on preventing or treating AD pathology. The present study investigated the effects of curcumin and 2 novel curcumin derivatives, FMeC1 and FMeC2, on AD pathology in APPswe/PS1dE9 double transgenic mice. Mice fed a chow diet that contained FMeC1 for 6 months showed a reduction in insoluble Aβ deposits and glial cell activity together with reduced cognitive deficits, compared to animals receiving a control diet or with curcumin or FMeC2 in their diet. Both curcumin and FMeC1 modulated the formation of Aβ aggregates; however, only FMeC1 significantly attenuated the cell toxicity of Aβ. These results indicate that FMeC1 may have potential for preventing AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cognition; Curcumin; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy; Neuroglia; Presenilin-1; Protein Aggregation, Pathological

Curcumin is a promising compound that can be used as a theranostic agent to aid research in Alzheimer's disease. Beyond its ability to bind to amyloid plaques, the compound can also cross the blood-brain barrier. Presently, curcumin can be applied only to animal models, as the formulation needed for iv injection renders it unfit for human use. Here, we describe a novel technique to aerosolize a curcumin derivative, FMeC1, and facilitate its safe delivery to the brain. Aside from the translational applicability of this approach, a study in the 5XFAD mouse model suggested that inhalation exposure to an aerosolized FMeC1 modestly improved the distribution of the compound in the brain. Additionally, immunohistochemistry data confirms that following aerosol delivery, FMeC1 binds amyloid plaques expressed in the hippocampal areas and cortex.

Topics: Administration, Inhalation; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain; Curcumin; Diagnostic Imaging; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Plaque, Amyloid; Presenilin-1; Tissue Distribution

Two fluorescent switchable diarylethene derivatives which exhibit high affinity for amyloid-β aggregates with the increase of fluorescence intensity were reported. Moreover, the probes show excellent photochromic and anti-photobleaching properties both in vitro and in vivo.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Curcumin; Fluorescent Dyes; Humans; Microscopy, Fluorescence

Diagnosis of Alzheimer's disease (AD) can be performed with the assistance of amyloid imaging. The current method relies on positron emission tomography (PET), which is expensive and exposes people to radiation, undesirable features for a population screening method. Magnetic resonance imaging (MRI) is cheaper and is not radioactive. Our approach uses magnetic nanoparticles (MNPs) made of superparamagnetic iron oxide (SPIO) conjugated with curcumin, a natural compound that specifically binds to amyloid plaques. Coating of curcumin-conjugated MNPs with polyethylene glycol-polylactic acid block copolymer and polyvinylpyrrolidone by antisolvent precipitation in a multi-inlet vortex mixer produces stable and biocompatible curcumin magnetic nanoparticles (Cur-MNPs) with mean diameter <100 nm. These nanoparticles were visualized by transmission electron microscopy and atomic force microscopy, and their structure and chemistry were further characterized by X-ray diffraction, thermogravimetric analysis, X-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectrometry, and Fourier transform infrared spectroscopy. Cur-MNPs exhibited no cytotoxicity in either Madin-Darby canine kidney (MDCK) or differentiated human neuroblastoma cells (SH-SY5Y). The Papp of Cur-MNPs was 1.03 × 10(-6) cm/s in an in vitro blood-brain barrier (BBB) model. Amyloid plaques could be visualized in ex vivo T2*-weighted magnetic resonance imaging (MRI) of Tg2576 mouse brains after injection of Cur-MNPs, and no plaques could be found in non-transgenic mice. Immunohistochemical examination of the mouse brains revealed that Cur-MNPs were co-localized with amyloid plaques. Thus, Cur-MNPs have the potential for non-invasive diagnosis of AD using MRI.

Topics: Adsorption; Alzheimer Disease; Animals; Cell Line, Tumor; Cell Membrane Permeability; Curcumin; Disease Models, Animal; Dogs; Humans; Immunohistochemistry; Madin Darby Canine Kidney Cells; Magnetic Resonance Imaging; Magnetite Nanoparticles; Mice, Transgenic; Particle Size; Photoelectron Spectroscopy; Plaque, Amyloid; Polyethylene Glycols; Spectrometry, Mass, Secondary Ion; Spectroscopy, Fourier Transform Infrared; Thermogravimetry; X-Ray Diffraction

Curcumin, a chemical constituent present in the spice turmeric, is known to prevent the aggregation of amyloid peptide implicated in the pathophysiology of Alzheimer's disease. While curcumin is known to bind directly to various amyloid aggregates, no systematic investigations have been carried out to understand its ability to bind to the amyloid aggregates including oligomers and fibrils. In this study, we constructed computational models of (i) Aβ hexapeptide (16) KLVFFA(21) octamer steric-zipper β-sheet assembly and (ii) full-length Aβ fibril β-sheet assembly. Curcumin binding in these models was evaluated by molecular docking and molecular dynamics (MD) simulation studies. In both the models, curcumin was oriented in a linear extended conformation parallel to fiber axis and exhibited better stability in the Aβ hexapeptide (16) KLVFFA(21) octamer steric-zipper model (Ebinding  = -10.05 kcal/mol) compared to full-length Aβ fibril model (Ebinding  = -3.47 kcal/mol). Analysis of MD trajectories of curcumin bound to full-length Aβ fibril shows good stability with minimum Cα-atom RMSD shifts. Interestingly, curcumin binding led to marked fluctuations in the (14) HQKLVFFA(21) region that constitute the fibril spine with RMSF values ranging from 1.4 to 3.6 Å. These results show that curcumin binding to Aβ shifts the equilibrium in the aggregation pathway by promoting the formation of non-toxic aggregates.

Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid beta-Peptides; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Curcuma; Curcumin; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Peptide Fragments; Protein Binding

Topics: Alzheimer Disease; Amino Acid Sequence; Antiviral Agents; Brain; Curcumin; Herpesvirus 1, Human; Humans; Models, Biological; Molecular Sequence Data

Liposomes with cardiolipin (CL) and wheat germ agglutinin (WGA) were developed to permeate the blood-brain barrier and treat Alzheimer's disease. WGA-conjugated and CL-incorporated liposomes (WGA-CL-liposomes) were used to transport nerve growth factor (NGF) and curcumin (CUR) across a monolayer of human brain-microvascular endothelial cells regulated by human astrocytes and to protect SK-N-MC cells against apoptosis induced by β-amyloid1-42 (Aβ(1-42)) fibrils. An increase in the CL mole percentage in lipids increased the liposomal diameter, absolute zeta potential value, entrapment efficiency of NGF and CUR, release of NGF, biocompatibility, and viability of SK-N-MC cells with Aβ(1-42), but decreased the atomic ratio of nitrogen to phosphorus and release of CUR. In addition, an increase in the WGA concentration for grafting enhanced the liposomal diameter, atomic ratio of nitrogen to phosphorus, and permeability of NGF and CUR across the blood-brain barrier, but reduced the absolute zeta potential value and biocompatibility. WGA-CL-liposomes carrying NGF and CUR could be promising colloidal delivery carriers for future clinical application in targeting the blood-brain barrier and inhibiting neurotoxicity.

Topics: Alzheimer Disease; Apoptosis; Cardiolipins; Curcumin; Humans; Liposomes; Nerve Growth Factor; Neurons; Wheat Germ Agglutinins

A series of new asymmetric curcumin analogues were synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. Our results showed that most of these synthetic compounds had better inhibitory properties against Aβ aggregation compared with curcumin, and better anti-oxidative properties compared with the reference compound Trolox through the study of oxygen radical absorbance capacity (ORAC). Some compounds showed good properties in selectively chelating metal ions such as copper and iron. Besides, some compounds were found to be able to dissociate Aβ protein which had already aggregated. The structure-activity relationships (SAR) of these synthetic compounds were studied. The present investigation indicated that our synthetic asymmetric curcumin derivatives could be potential multifunctional agents for the treatment of Alzheimer's disease (AD).

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Antioxidants; Cell Line, Tumor; Chelating Agents; Chromans; Copper; Curcumin; Drug Evaluation; Humans; Microscopy, Electron, Transmission; Molecular Structure; Neuroprotective Agents; Oxygen; Peptide Fragments; Protein Aggregates; Spectrum Analysis; Structure-Activity Relationship

When Alzheimer's disease (AD) progresses, several pathological features arise including accumulation of misfolded protein aggregates [e.g., amyloid-β (Aβ) plaques], metal ion dyshomeostasis, and oxidative stress. These characteristics are recently suggested to be interconnected through a potential factor, metal-associated Aβ (metal-Aβ) species. The role of metal-Aβ species in AD pathogenesis remains unclear, however. To elucidate the contribution of metal-Aβ species to AD pathology, as well as to develop small molecules as chemical tools and/or theranostic (therapeutic and diagnostic) agents for this disease, curcumin (Cur), a natural product from turmeric, and its derivatives have been studied towards both metal-free and metal-induced Aβ aggregation. Although Cur has indicated anti-amyloidogenic activities and antioxidant properties, its biological use has been hindered due to low solubility and stability in physiologically relevant conditions. Herein, we report the reactivity of Cur and its derivatives (Gd-Cur, a potential multimodal Aβ imaging agent; Cur-S, a water soluble derivative of Cur that has substitution at the phenolic hydroxyls) with metal-free Aβ and metal-Aβ species. Our results and observations indicate that Gd-Cur could modulate Cu(II)-triggered Aβ aggregation more noticeably over metal-free or Zn(II)-induced analogues; however, Cur-S was not observed to noticeably modulate Aβ aggregation with and without metal ions. Overall, our studies present information that could aid in optimizing the molecular scaffold of Cur for the development of chemical tools or theranostics for metal-Aβ species.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Capillary Permeability; Cell Line, Tumor; Cell Survival; Copper; Curcumin; Gadolinium; Mice; Molecular Structure; Neuroprotective Agents; Peptide Fragments; Protein Aggregates; Zinc

Currently, there is no gadolinium-based contrast agent available for conventional magnetic resonance imaging (MRI) detection of amyloidal beta (Aβ) plaques in Alzheimer's disease (AD). Its timely finding would be vital for patient survival and quality of life. Curcumin (CUR), a common Indian spice effectively binds to Aβ plaques which is a hallmark of AD. To address this binding, we have designed a novel nanoimaging agent (NIA) based on nature-derived poly(β-l-malic acid) (PMLA) containing covalently attached gadolinium-DOTA(Gd-DOTA) and nature-derived CUR. The all-in-one agent recognizes and selectively binds to Aβ plaques and is detected by MRI. It efficiently detected Aβ plaques in human and mouse samples by an ex vivo staining. The method can be useful in clinic for safe and noninvasive diagnosis of AD.

Topics: Alzheimer Disease; Animals; Brain; Contrast Media; Curcumin; Heterocyclic Compounds; Humans; Magnetic Resonance Imaging; Malates; Mice; Organometallic Compounds; Plaque, Amyloid; Polymers

Three different amyloid targeting ligands, previously shown to exhibit amyloid specific properties, have been used to develop amyloid -targeted nanoliposomes (AT-NLs. For this a MAb against Aβ-peptides (Aβ-MAb (immobilized on NLs at 0.015 and 0.05 mol %, and two different curcumin-lipid derivatives were attached to the surface of preformed NLs or incorporated in NL membranes during their formation. Following physicochemical characterization, these AT-NLs were studied for their ability to inhibit or delay amyloid peptide aggregation -using the thioflavin-T assay, and for their potential to reverse amyloid-induced (and Zn, or, amyloid + Zn cytotoxicity, on wild type (N2aWT and transformed (N2aAPP neuroblastoma cells, applying the MTT assay. Experimental results reveal that all formulations were found to strongly delay amyloid peptide aggregation (with no significant differences between the different AT-NL types. However, although Aβ-MAb-NLs significantly reversed amyloid-induced cytotoxicity in all cases, both curcumin-NL types did not reverse Zn-induced, nor Zn+Aβ-induced cytotoxicity in N2aWT cells, suggesting lower activity against synthetic-Aβ peptides (compared to endogenous Aβ peptides; perhaps due to different affinity towards different (aggregation stages of peptide species (monomers, oligomers, fibrils, etc. Taken into account that the aggregation stage of amyloid species is an important determinant of their toxicity, the importance of the affinity of each AT-NL type towards specific species, is highlighted.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Antibodies, Monoclonal; Cell Line, Tumor; Cell Survival; Curcumin; Drug Evaluation, Preclinical; Humans; Ligands; Liposomes; Mice; Nanoparticles; Toxicity Tests

Caspase-3 has been identified as a key mediator of neuronal apoptosis. The present study identifies caspase-3 as a common player involved in the regulation of multineurodegenerative disorders, namely, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The protein interaction network prepared using STRING database provides a strong evidence of caspase-3 interactions with the metabolic cascade of the said multineurodegenerative disorders, thus characterizing it as a potential therapeutic target for multiple neurodegenerative disorders. In silico molecular docking of selected nonpeptidyl natural compounds against caspase-3 exposed potent leads against this common therapeutic target. Rosmarinic acid and curcumin proved to be the most promising ligands (leads) mimicking the inhibitory action of peptidyl inhibitors with the highest Gold fitness scores 57.38 and 53.51, respectively. These results were in close agreement with the fitness score predicted using X-score, a consensus based scoring function to calculate the binding affinity. Nonpeptidyl inhibitors of caspase-3 identified in the present study expeditiously mimic the inhibitory action of the previously identified peptidyl inhibitors. Since, nonpeptidyl inhibitors are preferred drug candidates, hence, discovery of natural compounds as nonpeptidyl inhibitors is a significant transition towards feasible drug development for neurodegenerative disorders.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Apoptosis; Caspase 3; Caspase Inhibitors; Cinnamates; Curcumin; Depsides; Humans; Huntington Disease; Ligands; Molecular Docking Simulation; Neurodegenerative Diseases; Parkinson Disease; Rosmarinic Acid

Alzheimer's disease (AD) is a complex disease in which a single monofunctional 'targeted' drug is uneffective for management. Hybrid drugs that impact multiple targets simultaneously are better at controlling such complex disease systems. Hybrid agents were synthesized through the combination of the steroid moiety with curcumin molecule. Also novel curcumin analogues containing promising heterocyclic nucleus fused to the essential pharmacophoric feature of the curcumin moiety, were synthesized. The aim of the present study was extended to elucidate the efficacy of these novel synthesized compounds in the regression of AD induced in adult female albino rats. The results revealed that treatment of AD groups with compounds 3, 5, 8c or rivastigmin experienced significant increase in brain Ach, GSH, paraoxenase and BCL2 levels with respect to untreated group associated with significant decrease in brain AchE activity, urinary 8-OHG level, serum Caspase-3 level and brain P53 level relative to the untreated group. Immunohistochemical investigation revealed that the selected treatments caused marked increase in ChAT positive cells. These findings were documented by the histological investigation of the brain tissue. The activity of tested compounds showed gradual increase from compound b followed by compound 8c then compound 5. The anti-cholinesterase potential, anti-oxidant properties and anti-apoptotic activity are responsible for the anti-Alzheimer's disease potential of these compounds.

Topics: Acetylcholine; Alzheimer Disease; Animals; Antioxidants; Biomarkers; Brain; Caspase 3; Chemistry Techniques, Synthetic; Choline O-Acetyltransferase; Curcumin; Female; Oxidants; Proto-Oncogene Proteins c-bcl-2; Rats; Steroids; Tumor Suppressor Protein p53

Curcumin, the most active component of turmeric, has various beneficial properties, such as antioxidant, anti-inflammatory, and antitumor effects. Previous studies have suggested that curcumin reduces the levels of amyloid and oxidized proteins and prevents memory deficits and thus is beneficial to patients with Alzheimer's disease (AD). However, the molecular mechanisms underlying curcumin's effect on cognitive functions are not well-understood. In the present study, we examined the working memory and spatial reference memory in rats that received a ventricular injection of amyloid-β1-42 (Aβ1-42), representing a rodent model of Alzheimer's disease (AD). The rats treated with Aβ1-42 exhibited obvious cognitive deficits in behavioral tasks. Chronic (seven consecutive days, once per day) but not acute (once a day) curcumin treatments (50, 100, and 200 mg/kg) improved the cognitive functions in a dose-dependent manner. In addition, the beneficial effect of curcumin is accompanied by increased BDNF levels and elevated levels of phosphorylated ERK in the hippocampus. Furthermore, the cognition enhancement effect of curcumin could be mimicked by the overexpression of BDNF in the hippocampus and blocked by either bilateral hippocampal injections with lentiviruses that express BDNF shRNA or a microinjection of ERK inhibitor. These findings suggest that chronic curcumin ameliorates AD-related cognitive deficits and that upregulated BDNF-ERK signaling in the hippocampus may underlie the cognitive improvement produced by curcumin.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain-Derived Neurotrophic Factor; Cognition; Curcumin; Disease Models, Animal; Male; MAP Kinase Signaling System; Maze Learning; Memory Disorders; Memory, Short-Term; Neuroprotective Agents; Peptide Fragments; Rats; Rats, Sprague-Dawley; Signal Transduction; Spatial Memory

In this study, a novel low density lipoprotein (LDL)-mimic nanostructured lipid carrier (NLC) modified with lactoferrin (Lf) and loaded with curcumin (Cur) was designed for brain-targeted delivery, and its effect on controlling the progression of Alzheimer's disease (AD) in rats was evaluated. NLC with the composition resembling the lipid portion of LDL was prepared by using solvent evaporation method. Lf was adsorbed onto the surface of NLC via electrostatic interaction to yield Lf modified-NLC (Lf-mNLC) as the LDL-mimic nanocarrier. In order to make sure more Lf was adsorbed on the surface of NLC, negatively charged carboxylated polyethylene glycol (100) monostearate (S100-COOH) was synthesized and anchored into NLC. Different levels of S100-COOH (0-0.02 mmol) and Lf modified NLC (0.5-2.5 mg/mL of Lf solution) were prepared and characterized. The uptake and potential cytotoxicities of different preparations were investigated in the brain capillary endothelial cells (BCECs). An AD model of rats was employed to evaluate the therapeutic effects of Lf-mNLC. The results indicate that Lf-mNLC with a high level of Lf showed the maximum uptake in BCECs (1.39 folds greater than NLC) as cellular uptake of Lf-mNLC by BCECs was found to be mediated by the Lf receptor. FRET studies showed Cur still wrapped inside NLC after uptake by BCECs, demonstrating stability of the carrier as it moved across the BBB. Ex vivo imaging studies exposed Lf-mNLC could effectively permeate BBB and preferentially accumulate in the brain (2.78 times greater than NLC). Histopathological evaluation confirmed superior efficacy of Lf-mNLC in controlling the damage associated with AD. In conclusion, Lf-mNLC is a promising drug delivery system for targeting therapy of brain disease.

Topics: Alzheimer Disease; Animals; Cells, Cultured; Curcumin; Drug Carriers; Drug Delivery Systems; Lipoproteins, LDL; Malondialdehyde; Mice; Mice, Inbred ICR; Molecular Mimicry; Nanoparticles; Rats; Rats, Sprague-Dawley; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet; Tissue Distribution

Multiple pathogenic factors have been suggested to play a role in the development of Alzheimer's disease (AD). The multifactorial nature of AD also suggests the potential use of compounds with polypharmacology as effective disease-modifying agents. Recently, we have developed a bivalent strategy to include cell membrane anchorage into the molecular design. Our results demonstrated that the bivalent compounds exhibited multifunctional properties and potent neuroprotection in a cellular AD model. Herein, we report the mechanistic exploration of one of the representative bivalent compounds, 17MN, in MC65 cells. Our results established that MC65 cells die through a necroptotic mechanism upon the removal of tetracycline (TC). Furthermore, we have shown that mitochondrial membrane potential and cytosolic Ca2+ levels are increased upon removal of TC. Our bivalent compound 17MN can reverse such changes and protect MC65 cells from TC removal induced cytotoxicity. The results also suggest that 17MN may function between the Aβ species and RIPK1 in producing its neuroprotection. Colocalization studies employing a fluorescent analog of 17MN and confocal microscopy demonstrated the interactions of 17MN with both mitochondria and endoplasmic reticulum, thus suggesting that 17MN exerts its neuroprotection via a multiple-site mechanism in MC65 cells. Collectively, these results strongly support our original design rationale of bivalent compounds and encourage further optimization of this bivalent strategy to develop more potent analogs as novel disease-modifying agents for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Brain; Calcium; Caspase 3; Cell Line, Tumor; Cholesterol; Curcumin; Endoplasmic Reticulum; Humans; Male; Membrane Potential, Mitochondrial; Mice, Inbred C57BL; Molecular Structure; Neuroprotective Agents; Peptide Fragments; Receptor-Interacting Protein Serine-Threonine Kinases

In recent years, there has been growing interest in the near-infrared (NIR) fluorescence imaging of tau fibrils for the early diagnosis of Alzheimer's disease (AD). In order to develop a curcumin-based NIR fluorescent probe for tau fibrils, structural modification of the curcumin scaffold was attempted by combining the following rationales: the curcumin derivative should preserve its binding affinity to tau fibrils, and, upon binding to tau fibrils, the probe should show favorable fluorescence properties. To meet these requirements, we designed a novel curcumin scaffold with various aromatic substituents. Among the series, the curcumin derivative with a (4-dimethylamino-2,6-dimethoxy)phenyl moiety showed a significant change in its fluorescence properties (22.9-fold increase in quantum yield; Kd, 0.77 μM; λem, 620 nm; Φ, 0.32) after binding to tau fibrils. In addition, fluorescence imaging of tau-green fluorescent protein-transfected SHSY-5Y cells with confirmed that detected tau fibrils in live cells.

Topics: Alzheimer Disease; Cell Line; Curcumin; Fluorescent Dyes; Humans; Microscopy, Confocal; Molecular Probes; Optical Imaging; Protein Aggregation, Pathological; Spectrophotometry, Infrared; tau Proteins

In an effort to combat the multifaceted nature of Alzheimer's disease (AD) progression, a series of multifunctional, bivalent compounds containing curcumin and diosgenin were designed, synthesized, and biologically characterized. Screening results in MC65 neuroblastoma cells established that compound 38 with a spacer length of 17 atoms exhibited the highest protective potency with an EC50 of 111.7 ± 9.0 nM. A reduction in protective activity was observed as spacer length was increased up to 28 atoms and there is a clear structural preference for attachment to the methylene carbon between the two carbonyl moieties of curcumin. Further study suggested that antioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formation may contribute to the neuroprotective outcomes. Additionally, compound 38 was found to bind directly to Aβ, similar to curcumin, but did not form complexes with the common biometals Cu, Fe, and Zn. Altogether, these results give strong evidence to support the bivalent design strategy in developing novel compounds with multifunctional ability for the treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzothiazoles; Cell Line, Tumor; Cell Survival; Curcumin; Diosgenin; Drug Design; Humans; Ligands; Neuroprotective Agents; Reactive Oxygen Species; Thiazoles

Evidence suggests that curcumin, the phytochemical agent in the spice turmeric, might be a potential therapy for Alzheimer's disease (AD). Its antioxidant, anti-inflammatory properties have been investigated extensively. Studies have also shown that curcumin can reduce amyloid pathology in AD. The underlying mechanism, however, is complex and is still being explored. In this study, we used the APPswe/PS1dE9 double transgenic mice, an AD model, to investigate the effects and mechanisms of curcumin in the prevention and treatment of AD. The water maze test indicated that curcumin can improve spatial learning and memory ability in mice. Immunohistochemical staining and Western blot analysis were used to test major proteins in β-amyloid aggregation, β-amyloid production, and β-amyloid clearance. Data showed that, 3 months after administration, curcumin treatment reduced Aβ40 , Aβ42 , and aggregation of Aβ-derived diffusible ligands in the mouse hippocampal CA1 area; reduced the expression of the γ-secretase component presenilin-2; and increased the expression of β-amyloid-degrading enzymes, including insulin-degrading enzymes and neprilysin. This evidence suggests that curcumin, as a potential AD therapeutic method, can reduce β-amyloid pathological aggregation, possibly through mechanisms that prevent its production by inhibiting presenilin-2 and/or by accelerating its clearance by increasing degrading enzymes such as insulin-degrading enzyme and neprilysin.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Curcumin; Disease Models, Animal; Immunohistochemistry; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic

Eight dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized. The antioxidant test revealed that the synthesized compounds had higher free radical scavenging activity towards both 2,2-diphenyl-1-picrylhydrazyl free radicals (DPPH) (IC50 1.5-29.9μM) and galvinoxyl radicals (IC50 4.9-41.1μM) than the lead compound curcumin. Besides, compound 3a could effectively inhibit the Aβ self-aggregation in vitro. Investigated in phosphate-buffered solutions (pH=7.4) in the presence or absence of 0.1% FBS 3a showed a good stability while curcumin did not. Furthermore, 3a showed a good lipophilicity (logP=3.48), suggesting a potential ability to penetrate the blood-brain-barrier. The aqueous solubility of the hydrochloride salt of 3a (16.7mg/mL) has also been significantly improved as compared with curcumin (<0.1mg/mL).

Topics: Alzheimer Disease; Antioxidants; Curcumin; Drug Design; Molecular Structure

With the trend of an increasing aged population worldwide, Alzheimer's disease (AD), an age-related neurodegenerative disorder, as one of the major causes of dementia in elderly people is of growing concern. Despite the many hard efforts attempted during the past several decades in trying to elucidate the pathological mechanisms underlying AD and putting forward potential therapeutic strategies, there is still a lack of effective treatments for AD. The efficacy of many potential therapeutic drugs for AD is of main concern in clinical practice. For example, large bodies of evidence show that the anti-tumor histone deacetylase (HDAC) inhibitor, suberoylanilidehydroxamic acid (SAHA), may be of benefit for the treatment of AD; however, its extensive inhibition of HDACs makes it a poor therapeutic. Moreover, the natural flavonoid, curcumin, may also have a potential therapeutic benefit against AD; however, it is plagued by low bioavailability. Therefore, the integrative effects of SAHA and curcumin were investigated as a protection against amyloid-beta neurotoxicity in vitro. We hypothesized that at low doses their synergistic effect would improve therapeutic selectivity, based on experiments that showed that at low concentrations SAHA and curcumin could provide comprehensive protection against Aβ25-35-induced neuronal damage in PC12 cells, strongly implying potent synergism. Furthermore, network analysis suggested that the possible mechanism underlying their synergistic action might be derived from restoration of the damaged functional link between Akt and the CBP/p300 pathway, which plays a crucial role in the pathological development of AD. Thus, our findings provided a feasible avenue for the application of a synergistic drug combination, SAHA and curcumin, in the treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Cell Survival; CREB-Binding Protein; Curcumin; Disease Progression; Drug Synergism; E1A-Associated p300 Protein; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Histone Deacetylase Inhibitors; Neurons; Neuroprotective Agents; Nylons; Oxidative Stress; PC12 Cells; Pyrroles; Rats

Neurogenesis, a process of generation of new neurons, is reported to be reduced in several neurodegenerative disorders including Alzheimer's disease (AD). Induction of neurogenesis by targeting endogenous neural stem cells (NSC) could be a promising therapeutic approach to such diseases by influencing the brain self-regenerative capacity. Curcumin, a neuroprotective agent, has poor brain bioavailability. Herein, we report that curcumin-encapsulated PLGA nanoparticles (Cur-PLGA-NPs) potently induce NSC proliferation and neuronal differentiation in vitro and in the hippocampus and subventricular zone of adult rats, as compared to uncoated bulk curcumin. Cur-PLGA-NPs induce neurogenesis by internalization into the hippocampal NSC. Cur-PLGA-NPs significantly increase expression of genes involved in cell proliferation (reelin, nestin, and Pax6) and neuronal differentiation (neurogenin, neuroD1, neuregulin, neuroligin, and Stat3). Curcumin nanoparticles increase neuronal differentiation by activating the Wnt/β-catenin pathway, involved in regulation of neurogenesis. These nanoparticles caused enhanced nuclear translocation of β-catenin, decreased GSK-3β levels, and increased promoter activity of the TCF/LEF and cyclin-D1. Pharmacological and siRNA-mediated genetic inhibition of the Wnt pathway blocked neurogenesis-stimulating effects of curcumin. These nanoparticles reverse learning and memory impairments in an amyloid beta induced rat model of AD-like phenotypes, by inducing neurogenesis. In silico molecular docking studies suggest that curcumin interacts with Wif-1, Dkk, and GSK-3β. These results suggest that curcumin nanoparticles induce adult neurogenesis through activation of the canonical Wnt/β-catenin pathway and may offer a therapeutic approach to treating neurodegenerative diseases such as AD, by enhancing a brain self-repair mechanism.

Topics: Alzheimer Disease; Animals; beta Catenin; Cognition Disorders; Curcumin; Disease Models, Animal; Microscopy, Electron, Transmission; Nanoparticles; Rats; Reelin Protein; Wnt Proteins

Alzheimer's disease (AD) is the most common type of presenile and senile dementia. The human β-amyloid precursor cleavage enzyme (BACE-1) is a key enzyme responsible for amyloid plaque production, which implicates the progress and symptoms of AD. Here we assessed the anti-BACE-1 and behavioral activities of curcuminoids from rhizomes of Curcuma longa (Zingiberaceae), diarylalkyls curcumin (CCN), demethoxycurcumin (DMCCN), and bisdemethoxycurcumin (BDMCCN) against AD Drosophila melanogaster models.. Neuro-protective ability of the curcuminoids was assessed using Drosophila melanogaster model system overexpressing BACE-1 and its substrate APP in compound eyes and entire neurons. Feeding and climbing activity, lifespan, and morphostructural changes in fly eyes also were evaluated.. BDMCCN has the strongest inhibitory activity toward BACE-1 with 17 μM IC50, which was 20 and 13 times lower than those of CCN and DMCCN respectively. Overexpression of APP/BACE-1 resulted in the progressive and measurable defects in morphology of eyes and locomotion. Remarkably, supplementing diet with either 1 mM BDMCCN or 1 mM CCN rescued APP/BACE1-expressing flies and kept them from developing both morphological and behavioral defects. Our results suggest that structural characteristics, such as degrees of saturation, types of carbon skeleton and functional group, and hydrophobicity appear to play a role in determining inhibitory potency of curcuminoids on BACE-1.. Further studies will warrant possible applications of curcuminoids as therapeutic BACE-1 blockers.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Behavior, Animal; Curcuma; Curcumin; Disease Models, Animal; Drosophila; Eye; Female; Humans; Longevity; Male; Plant Extracts; Rhizome

Amyloid β (Aβ) fibrillar deposits in the brain are a hallmark of Alzheimer disease (AD). Curcumin, a common ingredient of Asian spices, is known to disrupt Aβ fibril formation and to reduce AD pathology in mouse models. Understanding the structural changes induced by curcumin can potentially lead to AD pharmaceutical agents with inherent bio-compatibility. Here, we use solid-state NMR spectroscopy to investigate the structural modifications of amyloid β(1-42) (Aβ42) aggregates induced by curcumin. We find that curcumin induces major structural changes in the Asp-23-Lys-28 salt bridge region and near the C terminus. Electron microscopy shows that the Aβ42 fibrils are disrupted by curcumin. Surprisingly, some of these alterations are similar to those reported for Zn(2+) ions, another agent known to disrupt the fibrils and alter Aβ42 toxicity. Our results suggest the existence of a structurally related family of quasi-fibrillar conformers of Aβ42, which is stabilized both by curcumin and by Zn(2+.)

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cells, Cultured; Curcumin; Enzyme Inhibitors; Female; Humans; Mice; Nuclear Magnetic Resonance, Biomolecular; Peptide Fragments; Protein Stability; Protein Structure, Secondary; Rats; Rats, Wistar; Zinc

Curcumin is a neuroprotective compound that inhibits the formation of amyloid oligomers and fibrils and binds to β-amyloid plaques in Alzheimer's disease (AD). We aimed to synthesize an (18)F-labeled curcumin derivate ([(18)F]4) and to characterize its positron emission tomography (PET) tracer-binding properties to β-amyloid plaques in a transgenic APP23 mouse model of AD.. We utilized facile one-pot synthesis of [(18)F]4 using nucleophilic (18)F-fluorination and click chemistry. Binding of [(18)F]4 to β-amyloid plaques in the transgenic APP23 mouse brain cryosections was studied in vitro using heterologous competitive binding against PIB. [(18)F]4 uptake was studied ex vivo in rodents and in vivo using PET/computed tomography of transgenic APP23 and wild-type control mice.. The radiochemical yield of [(18)F]4 was 21 ± 11%, the specific activity exceeded 1TBq/μmol, and the radiochemical purity exceeded 99.3% at the end of synthesis. In vitro studies of [(18)F]4 with the transgenic APP23 mouse revealed high β-amyloid plaque binding. In vivo and ex vivo studies demonstrated that [(18)F]4 has fast clearance from the blood, moderate metabolism but low blood-brain barrier (BBB) penetration.. [(18)F]4 was synthesized in high yield and excellent quality. In vitro studies, metabolite profile, and fast clearance from the blood indicated a promising tracer for Aβ imaging. However, [(18)F]4 has low in vivo BBB penetration and thus further studies are needed to reveal the reason for this and to possibly overcome this issue.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Curcumin; Fluorine Radioisotopes; Isotope Labeling; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Plaque, Amyloid; Positron-Emission Tomography; Protein Binding; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Tissue Distribution

Curcumin has been widely used for the prevention and treatment of Alzheimer's disease (AD), but its mechanism is still not clear. Inhibitory factors of axonal regeneration have been shown to cause a series of pathophysiological changes in the early period of AD. In this study, the co-receptor (Nogo receptor; NgR) of three axonal growth-inhibitory proteins was examined, and effects of curcumin on spatial learning and memory abilities and hippocampal axonal growth were investigated in amyloid β-protein (Aβ)1-40-induced AD rats. Results showed that the expression of NgR in the AD group significantly increased and the number of axonal protein-positive fibers significantly reduced. The spatial learning and memory abilities of AD rats were significantly improved in the curcumin group. Furthermore, hippocampal expressions of NgR mRNA and protein decreased, and the expression of axonal protein significantly increased. There was a negative correlation between the expression of NgR and axonal growth. Together, these results suggested that curcumin could improve the spatial learning and memory abilities of AD rats. The mechanism might be related with its lowering of hippocampal NgR expression and promoting axonal regeneration.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Axons; Curcumin; Disease Models, Animal; Gene Expression Regulation; GPI-Linked Proteins; Hippocampus; Male; Maze Learning; Myelin Proteins; Nogo Receptor 1; Rats; Receptors, Cell Surface; RNA, Messenger

Curcumin (CUR) and curcuminoids complexes labeled with fluorine-18 or technetium-99m have recently shown their potential as diagnostic tools for Alzheimer's disease. Gallium-68 is a positron-emitting, generator-produced radionuclide, and its properties can be exploited in situ in medical facilities without a cyclotron. Moreover, CUR showed a higher uptake in tumor cells compared to normal cells, suggesting potential diagnostic applications in this field. In spite of this, no studies using labeled CUR have been performed in this direction, so far. Herein, (68)Ga-labeled complexes with CUR and two curcuminoids, namely diacetyl-curcumin (DAC) and bis(dehydroxy)curcumin (bDHC), were synthesized and characterized by means of experimental and theoretical approaches. Moreover, a first evaluation of their affinity to synthetic β-amyloid fibrils and uptake by A549 lung cancer cells was performed to show the potential application of these new labeled curcuminoids in these diagnostic fields. The radiotracers were prepared by reacting (68)Ga(3+) obtained from a (68)Ge/(68)Ga generator with 1 mg/mL curcuminoids solutions. Reaction parameters (precursor amount, reaction temperature, and pH) were optimized to obtain high and reproducible radiochemical yield and purity. Stoichiometry and formation of the curcuminoid complexes were investigated by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, NMR, ultraviolet-visible, and fluorescence spectroscopy on the equivalent (nat)Ga-curcuminoids (nat = natural) complexes, and their structure was computed by theoretical density functional theory calculations. The analyses evidenced that CUR, DAC, and bDHC were predominantly in the keto-enol form and attested to Ga(L)2(+) species formation. Identity of the (68)Ga(L)2(+) complexes was confirmed by coelution with the equivalent (nat)Ga(L)2(+) complexes in ultrahigh-performance liquid chromatography analyses.(68)Ga(CUR)2(+), (68)Ga(DAC)2(+), and (68)Ga(bDHC)2(+) were highly (87 ± 4, 90 ± 1%) and moderately (48 ± 2%), respectively, retained by synthetic β-amyloid fibrils in vitro. All the Ga-curcuminoid complexes showed an uptake in A549 lung cancer cells, at least equivalent to the respective free curcuminoids, confirming potential applications as cancer-detecting radiotracers.

Topics: Alzheimer Disease; Cell Line, Tumor; Curcumin; Gallium Radioisotopes; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Neoplasms; Organometallic Compounds; Quantum Theory; Radiopharmaceuticals; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet

With the objective to formulate multifunctional nanosized liposomes to target amyloid deposits in Alzheimer Disease (AD) brains, a lipid-PEG-curcumin derivative was synthesized and characterized. Multifunctional liposomes incorporating the curcumin derivative and additionally decorated with a Blood Brain Barrier (BBB) transport mediator (anti-Transferin antibody) were prepared and characterized. The fluorescence intensity of curcumin derivative was found to increase notably when the curcumin moiety was in the form of a diisopropylethylamine (DIPEA) salt. Both curcumin-derivative liposomes and curcumin-derivative Anti-TrF liposomes showed a high affinity for the amyloid deposits, on post-mortem brains samples of AD patients. The ability of both liposomes to delay Aβ1-42 peptide aggregation was confirmed by Thioflavin assay. However, the decoration of the curcumin-derivative liposomes with the Anti-TrF improved significantly the intake by the BBB cellular model. Results verify that the attachment of an antibody on the curcumin-liposome surface does not block deposit staining or prevention of Aβ aggregation, while the presence of the curcumin-PEG-lipid conjugate does not reduce their brain-targeting capability substantially, proving the potential of such multifunctional NLs for application in Alzheimer disease treatment and diagnosis.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biological Transport; Blood-Brain Barrier; Brain; Curcumin; Humans; Liposomes; Molecular Targeted Therapy; Nanoparticles; Peptide Fragments; Polyethylene Glycols; Protein Multimerization; Protein Structure, Secondary

In our effort to develop effective neuroprotectants as potential treatments for Alzheimer's disease (AD), hybrid compounds of curcumin and melatonin, two natural products that have been extensively studied in various AD models, were designed, synthesized, and biologically characterized. A lead hybrid compound (7) was discovered to show significant neuroprotection with nanomolar potency (EC50 = 27.60 ± 9.4 nM) in MC65 cells, a cellular AD model. Multiple in vitro assay results established that 7 exhibited moderate inhibitory effects on the production of amyloid-β oligomers (AβOs) in MC65 cells, but not on the aggregation of Aβ species. It also exhibited significant antioxidative properties. Further mechanistic studies demonstrated that 7's antioxidant effects correlate well with its neuroprotective potency for MC65 cells, and these effects might be due to its interference with the interactions of AβOs within the mitochondria of MC65 cells. Furthermore, 7 was confirmed to cross the blood-brain barrier (BBB) and deliver a sufficient amount to brain tissue after oral administration. Collectively, these results strongly support the hybridization approach as an efficient strategy to help identify novel scaffolds with a desired pharmacology, and strongly encourage further optimization of 7 to develop more potent neuroprotectants for AD.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Brain; Capillary Permeability; Cell Line, Tumor; Cell Survival; Curcumin; Humans; Magnetic Resonance Spectroscopy; Male; Melatonin; Mice; Mitochondria; Molecular Structure; Neuroprotective Agents

This study was designed to investigate whether telomerase was involved in the neuroprotective effect of curcumin and Cur1. Alzheimer's disease is a consequence of an imbalance between the generation and clearance of amyloid-beta peptide in the brain. In this study, we used Aβ1-42 (10 µg/ml) to establish a damaged cell model, and curcumin and Cur1 were used in treatment groups. We measured cell survival and cell growth, intracellular oxidative stress and hTERT expression. After RNA interference, the effects of curcumin and Cur1 on cells were verified. Exposure to Aβ1-42 resulted in significant oxidative stress and cell toxicity, and the expression of hTERT was significantly decreased. Curcumin and Cur1 both protected SK-N-SH cells from Aβ1-42 and up-regulated the expression of hTERT. Furthermore, Cur1 demonstrated stronger protective effects than curcumin. However, when telomerase was inhibited by TERT siRNA, the neuroprotection by curcumin and Cur1 were ceased. Our study indicated that the neuroprotective effects of curcumin and Cur1 depend on telomerase, and thus telomerase may be a target for therapeutic effects of curcumin and Cur1.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Cell Survival; Curcumin; Humans; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Telomerase

Autophagy is a lysosomal degradation pathway, which is essential for cell survival, proliferation, differentiation and homeostasis. It is well known that beta-amyloid (Aβ) aggregation is one of key characteristics for Alzheimer's disease (AD), which triggers a complex pathological cascade, leading to neurodegeneration. Recent studies have shown that Aβ peptide is generated from amyloid β precursor protein (APP) during autophagic turnover of APP-rich organelles by autophagy. Aβ generation during normal autophagy is subsequently degraded by lysosomes. Curcumin, a nature plant extraction, has been reported to inhibit the generation and deposition of Aβ; however, the underlying mechanisms are not fully understood yet. In the present study, we reported that curcumin treatment not only attenuated cognitive impairment detected by Morris water maze test, but also inhibited the generation of Aβ investigated by immunohistochemistry in APP/PS1 double transgenic AD mice. Moreover, curcumin induced autophagy in the mice, evidenced by LC3 immunofluorescence analysis and western blot assays on LC3. Furthermore, we found that curcumin significantly decreased the expression of Phosphatidylinositol 3-Kinase (PI3K), phosphorylated Akt and rapamycin (mTOR) at protein levels, respectively. Taken together, our data suggests that curcumin inhibits Aβ generation and induces of autophagy by downregulating PI3K/Akt/mTOR signaling pathway, and further shows a neuroprotective effect. Meanwhile curcumin might be a candidate neuroprotective agent for AD patients treatment by inducing autophagy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Cognition; Curcumin; Disease Models, Animal; Down-Regulation; Female; Hippocampus; Male; Maze Learning; Memory; Mice, Transgenic; Neuroprotective Agents; Peptide Fragments; Phosphatidylinositol 3-Kinase; Presenilin-1; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

A series of novel 2-methoxy-phenyl dimethyl-carbamate derivatives were designed, synthesized and evaluated as site-activated MTDLs based on rivastigmine and curcumin. Most of them exhibited good to excellent AChE and BuChE inhibitory activities with sub-micromolar IC50 values. Among all the compounds, 6a demonstrated the most potent AChE inhibition with IC50 value of 0.097μM, which is about 20-fold than that of rivastigmine. In addition, the three selected compounds 5a, 6a and 6e demonstrated inhibitory activity against Aβ self-aggregation similar to cucurmin in TEM assay, which is obviously different from the weak activity of rivastigmine. Moreover, the hydrolysate of 6a (compound 7) also showed potent ABTS(+) scavenging and moderate copper ion chelating activity in vitro.

Topics: Acetylcholinesterase; Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Curcumin; Dose-Response Relationship, Drug; Drug Design; Ligands; Molecular Docking Simulation; Molecular Structure; Phenylcarbamates; Rivastigmine; Structure-Activity Relationship

In this report, we designed a highly bright bifunctional curcumin analogue CRANAD-28. In vivo two-photon imaging suggested that CRANAD-28 could penetrate the blood brain barrier (BBB) and label plaques and cerebral amyloid angiopathies (CAAs). We also demonstrated that this imaging probe could inhibit the crosslinking of amyloid beta induced either by copper or by natural conditions.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Brain; Copper; Curcumin; Humans; Ions; Mice; Mice, Transgenic; Photons; Protein Binding; Spectroscopy, Near-Infrared

To observe the changes in Aβ40, Aβ42 and ADDLs in brains of 3 month-old APPswe/PS1dE9 double transgenic mice after six-month intervention with curcumin, in order to discuss the neuroprotective effect of curcumin.. APPswe/PS1dE9dtg mice were randomly divided into the model group, the Rosiglitazone group (10 mg x kg(-1) x d(-1)) and curcumin high (400 mg x kg9-1) x d(-1)), medium (200 mg x kg(-1) x d(-1)) and low (100 mg x kg(-1) x d(-1)) dosage groups, with C57/BL6J mice of the same age and the same background in the normal control group. After 6 months, the immunohistochemical staining (IHC) and the Western blot method were used to observe the changes in positive cell of Aβ40, Aβ42 and ADDLs in hippocampal CA1 area, their distribution and protein expressions.. Both of the immunohistochemical staining and the Western blot method showed more positive cell of Aβ40, Aβ42 and ADDLs in hippocampal CA1 area and higher protein expressions in the model group than the normal group (P < 0.01). IHC showed a lower result in the Rosiglitazone group than the model group (P < 0.05), while Western blot showed a much lower result (P < 0.01). The number of Aβ40, Aβ42 and ADDLs positive cells and the protein expressions decreased in the curcumin high group, the medium group showed a significant decrease (P < 0.01), and the low dose group also showed reductions in the protein expressions of Aβ40 and Aβ42.. The six-month intervention with curcumin can significantly reduce the expressions of hippocampal Aβ40, Aβ42 and ADDLs in brains of APPswe/PS1dE9 double transgenic mice. Whether curcumin can impact Aβ cascade reaction by down-regulating expressions of Aβ40, Aβ42 and ADDLs and show the neuroprotective effect needs further studies.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Curcumin; Disease Models, Animal; Hippocampus; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Plant Extracts

Curcumin, a dietary polyphenol, has shown a potential to act on the symptoms of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, as a consequence of its antioxidant, anti-inflammatory and anti-protein aggregation properties. Unfortunately, curcumin undergoes rapid degradation at physiological pH into ferulic acid, vanillin and dehydrozingerone, making it an unlikely drug candidate. Here, we evaluated the ability of some curcumin by-products: dehydrozingerone (1), its O-methyl derivative (2), zingerone (3), and their biphenyl analogues (4-6) to interact with α-synuclein (AS), using CD and fluorescence spectroscopy. In addition, the antioxidant properties and the cytoprotective effects in rat pheochromocytoma (PC12) cells prior to intoxication with H2O2, MPP+ and MnCl2 were examined while the Congo red assay was used to evaluate the ability of these compounds to prevent aggregation of AS. We found that the biphenyl zingerone analogue (6) interacts with high affinity with AS and also displays the best antioxidant properties while the biphenyl analogues of dehydrozingerone (4) and of O-methyl-dehydrozingerone (5) are able to partially inhibit the aggregation process of AS, suggesting the potential role of a hydroxylated biphenyl scaffold in the design of AS aggregation inhibitors.

Topics: Adrenal Gland Neoplasms; alpha-Synuclein; Alzheimer Disease; Animals; Antioxidants; Cell Line, Tumor; Curcumin; Cytoprotection; Guaiacol; Parkinson Disease; Pheochromocytoma; Rats; Styrenes

The accumulation of intracellular β amyloid (Aβ) may be one of the factors leading to neuronal cell death in Alzheimer's disease (AD). Using a pyrazole called CNB-001, which was selected for its ability to reduce intracellular Aβ, we show that the activation of the eIF2α/ATF4 arm of the unfolded protein response is sufficient to degrade aggregated intracellular Aβ. CNB-001 is a potent inhibitor of 5-lipoxygenase (5-LOX), decreases 5-LOX expression, and increases proteasome activity. 5-LOX inhibition induces eIF2α and PERK (protein kinase R-like extracellular signal-regulated kinase) phosphorylation, and HSP90 and ATF4 levels. When fed to AD transgenic mice, CNB-001 also increases eIF2α phosphorylation and HSP90 and ATF4 levels, and limits the accumulation of soluble Aβ and ubiquitinated aggregated proteins. Finally, CNB-001 maintains the expression of synapse-associated proteins and improves memory. Therefore, 5-LOX metabolism is a key element in the promotion of endoplasmic reticulum dysfunction, and its inhibition under conditions of stress is sufficient to reduce proteotoxicity both in vivo and in vitro.

Topics: Activating Transcription Factor 4; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apomorphine; Arachidonate 5-Lipoxygenase; Behavior, Animal; Blotting, Western; Curcumin; Dopamine Agonists; Electrophoresis, Polyacrylamide Gel; Eukaryotic Initiation Factor-2; Humans; Lipoxygenase Inhibitors; Maze Learning; Mice; Mice, Transgenic; Peptide Fragments; Phosphorylation; Proteasome Endopeptidase Complex; Protein Folding; Pyrazoles; RNA, Messenger; Ubiquitin

To observe the effect of curcumin on the expression of PI3K (phosphatidylinositol-3-kinase, PI3K) and p-P3 K (phosphated phosphatidylinositol-3-kinase, p-PI3K) in the hippocampus of Alzheimer's disease (AD) model (APP/PS1 double transgenic) mice.. A total of 60 three-month-old APP/PS1 double transgenic mice were randomly divided into model group, rosiglitazone group(10 mg . kg-1 . d-1) and curcumin large(400 mg . kg-1 . d-1), medium(200 mg- kg-1 . d-1) and small(100 mg . kg-1 . d-1) dose group. Twelve C57BL/6J mice in the same age and genetic background as APP/PS1 double transgenic mice were used as normal control group. All the 6 groups of mice were intragastrically administered for 3 months. After 3 months, the expression of PI3K and p-PI3K were detected by immunohistochemistry and Western blot.. The expression of PI3K and p-PI3K positive cells in hippocampus CA1 region significantly decreased in model group compared with normal control group (P < 0. 05) , while compared with model group, PI3K and p-PI3K positive cells of all the curcumin intervention groups increased to varying degrees in hippocampus CA1 region,especially the middle dose group(P <0. 01). Besides,Western blot results of the curcumin high dose group were also increased obviously (P <0. 05).. Curcumin can recover the decreased PI3K and p-PI3K and improve the insulin-signaling transmission in the hippocampus of APP/PS1 double transgenic mice. The mechanism of curcumin maybe by regulating the insulin signal transduction to treat AD.

Topics: Alzheimer Disease; Animals; Curcumin; Disease Models, Animal; Hippocampus; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphatidylinositol 3-Kinases; Rosiglitazone; Thiazolidinediones

Through the dynamic detection of the concentration change of the urine Alzheimer-associated neuronal thread protein (AD7C-NTP) in the curcumin treated Alzheimer's disease (AD) model (APP/PS1 double transgenic) mice, the therapeutic effect of curcumin in AD was determined.. Thirty three-month-old APP /PS1 double transgenic mice were randomly divided into 5 groups, 6 in each group, the model group, rosiglitazone group(10 mg . kg-1 . d-1) , high(400 mg . kg -1 . d-1) , medium(200 mg . kg-1. d-1) and low(100 mg . kg-1 . d-1) dose curcumin groups. Six C57BL/6J mice in the same age and genetic background were used as normal control group. All the 6 groups of mice were intragastrically administered for 6 months. Urine samples were collected on 4 month, 5 month and 6 month after intragastric administration, respectively. The changes of urinary AD7C-NTP concentration were detected by enzyme-linked immunosorbent assay (ELISA).. The concentration of AD7C-NTP of each group was compared at the same time point, the concentration of model group is higher than normal control group (P <0.05) ; the concentration of other groups is lower than model group. The concentration of high curcumin dose group with 4 months treatment, has no statistical difference compared with model group. The AD7C-NTP concentration of each group was elevated with the age growth, and all concentrations of the treatment groups were lower than the model group at the same period. With the treatment of 4, 5 and 6 months, the concentration of the normal control group has significant difference with the treatment groups(P <0. 01). There have no statistical difference between all the groups with the treatment of 6 months compared with 5 months.. With the progression of the disease in AD mice, there are fluctuations in urinary AD7C-NTP concentration, the compound curcumin from traditional Chinese medicine can delay the progression of AD.

Topics: Alzheimer Disease; Animals; Curcumin; Enzyme-Linked Immunosorbent Assay; Mice; Mice, Transgenic; Nerve Tissue Proteins; Rosiglitazone; Thiazolidinediones

In this article, we first designed and synthesized curcumin-based near-infrared (NIR) fluorescence imaging probes for detecting both soluble and insoluble amyloid beta (Aβ) species and then an inhibitor that could attenuate cross-linking of Aβ induced by copper. According to our previous results and the possible structural stereohindrance compatibility of the Aβ peptide and the hydrophobic/hydrophilic property of the Aβ13-20 (HHQKLVFF) fragment, NIR imaging probe CRANAD-58 was designed and synthesized. As expected CRANAD-58 showed significant fluorescence property changes upon mixing with both soluble and insoluble Aβ species in vitro. In vivo NIR imaging revealed that CRANAD-58 was capable of differentiating transgenic and wild-type mice as young as 4 months old, the age that lacks apparently visible Aβ plaques and Aβ is likely in its soluble forms. According to our limited studies on the interaction mechanism between CRANAD-58 and Aβ, we also designed CRANAD-17 to attenuate the cross-linking of Aβ42 induced by copper. It is well-known that the coordination of copper with imidazoles on Histidine-13 and 14 (H13, H14) of Aβ peptides could initialize covalent cross-linking of Aβ. In CRANAD-17, a curcumin scaffold was used as an anchoring moiety to usher the designed compound to the vicinity of H13 and H14 of Aβ, and imidazole rings were incorporated to compete with H13/H14 for copper binding. The results of SDS-PAGE gel and Western blot indicated that CRANAD-17 was capable of inhibiting Aβ42 cross-linking induced by copper. This raises a potential for CRANAD-17 to be considered for AD therapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Copper; Curcumin; Drug Design; Female; Fluorescent Dyes; Mice; Mice, Transgenic; Molecular Structure; Spectrometry, Fluorescence

The synthesis and characterization of neutral mixed ligand complexes fac-[M(CO)3(P)(OO)] and cis-trans-[M(CO)2(P)2(OO)] (M = Re, (99m)Tc), with deprotonated acetylacetone or curcumin as the OO donor bidentate ligands and a phosphine (triphenylphosphine or methyldiphenylphosphine) as the monodentate P ligand, is described. The complexes were synthesized through the corresponding fac-[M(CO)3(H2O)(OO)] (M = Re, (99m)Tc) intermediate aqua complex. In the presence of phosphine, replacement of the H2O molecule of the intermediate complex at room temperature generates the neutral tricarbonyl monophosphine fac-[Re(CO)3(P)(OO)] complex, while under reflux conditions further replacement of the trans to the phosphine carbonyl generates the new stable dicarbonyl bisphosphine complex cis-trans-[Re(CO)2(P)2(OO)]. The Re complexes were fully characterized by elemental analysis, spectroscopic methods, and X-ray crystallography showing a distorted octahedral geometry around Re. Both the monophosphine and the bisphosphine complexes of curcumin show selective binding to β-amyloid plaques of Alzheimer's disease. At the (99m)Tc tracer level, the same type of complexes, fac-[(99m)Tc(CO)3(P)(OO)] and cis-trans-[(99m)Tc(CO)2(P)2(OO)], are formed introducing new donor combinations for (99m)Tc(I). Overall, β-diketonate and phosphine constitute a versatile ligand combination for Re(I) and (99m)Tc(I), and the successful employment of the multipotent curcumin as β-diketone provides a solid example of the pharmacological potential of this system.

Topics: Alzheimer Disease; Binding Sites; Coordination Complexes; Crystallography, X-Ray; Curcumin; Humans; Ligands; Models, Molecular; Pentanones; Phosphines; Plaque, Amyloid; Protons

To explore the effects of curcumin on the expression of high mobility group box1 (HMGB1) , cell viability and morphology in a cellular model of Alzheimer's disease (AD).. Cultured PC12 cells in logarithmic growth phase were divided into 5 groups: normal cell group (A, non-treatment), model control group (B, 20 µmol/L Aβ25-35), curcumin treatment group (C, 20 µmol/L Aβ25-35+1 µmol/L Cur), Aβ25-35+rHMG1 (D, 20 µmol/L Aβ25-35+500 ng/ml HMGB1) and solvent control group (E, 20 µmol/L Aβ25-35+1 µl/ml DMSO). Cell viability was examined by methyl thiazolyl tetrazolium (MTT). And the cellular expression and distribution of HMGB1 were detected by immunofluorescence and Western blot 24 hours later.. Compared with group A, the levels of cell viability in groups B, D and E significantly declined (0.76 ± 0.06, 0.63 ± 0.02, 0.75 ± 0.03 vs 1.22 ± 0.06, P < 0.05) while the expression of HMGB1 increased (1.19 ± 0.14, 1.12 ± 0.16, 1.16 ± 0.09 vs 0.85 ± 0.04, P < 0.05). Compared with group B, cell viability in group C significantly increased by 33% (1.01 ± 0.05, P < 0.05) while the expression of HMGB1 declined by 31% (0.78 ± 0.03, P < 0.05). A larger amount of extracellular HMGB1 was released in group B compared with group A. And the extracellular release of HMGB1 declined less in group C versus group B.. Curcumin may reduce Aβ25-35-induced cytotoxicity through a down-regulated expression of HMGB1 and an inhibition of extracellular release of HMGB1 in PC12 cell.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Survival; Curcumin; HMGB1 Protein; PC12 Cells; Peptide Fragments; Rats

Recent studies have demonstrated several biological activities of curcumin with therapeutic potential against Alzheimer's disease, among them the inhibition of the enzyme acetylcholinesterase (AChE). Aiming at identifying the chemical features relevant for this activity, the inhibition of curcumin and a set of 7 derivatives against AChE of E. electricus was measured. These derivatives presented lower activity than curcumin, allowing for the identification of possible unfavorable enzyme-inhibitor interactions. Our computational approach was to dock the molecules to the active site of AChE, followed by an analysis of hydrogen bonds and close contacts to relevant aromatic amino acid residues. To account for inhibitory activity, we sought to define the common structural features between known acetylcholinesterase inhibitors and the tested derivatives. A pharmacophore model was generated, which consisted of two hydrophobic, one aromatic and one hydrogen bond acceptor features. We conclude that the presence of two aromatic rings and the distance between them, allows curcumin and its derivatives to favorably interact with both the quaternary and peripheral sites of AChE. Hydrogen bonds can be formed with the quaternary and acyl sites, which should further stabilize the complex. The acylation of the hydroxyl groups and the reduction of the conjugated double bonds lowered the inhibitory activity, pointing to the modification of the keto-enol moiety as the best alternative for the design of more potent curcumin derivatives as acetylcholinesterase inhibitors.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Curcumin; Humans; Molecular Docking Simulation; Torpedo

Accumulation of amyloid peptide (Aβ) in senile plaques is a hallmark lesion of Alzheimer disease (AD). The design of molecules able to target the amyloid pathology in tissue is receiving increasing attention, both for diagnostic and for therapeutic purposes. Curcumin is a fluorescent molecule with high affinity for the Aβ peptide but its low solubility limits its clinical use. Curcumin-conjugated nanoliposomes, with curcumin exposed at the surface, were designed. They appeared to be monodisperse and stable. They were non-toxic in vitro, down-regulated the secretion of amyloid peptide and partially prevented Aβ-induced toxicity. They strongly labeled Aβ deposits in post-mortem brain tissue of AD patients and APPxPS1 mice. Injection in the hippocampus and in the neocortex of these mice showed that curcumin-conjugated nanoliposomes were able to specifically stain the Aβ deposits in vivo. Curcumin-conjugated nanoliposomes could find application in the diagnosis and targeted drug delivery in AD.. In this preclinical study, curcumin-conjugated nanoliposomes were investigated as possible diagnostics and targeted drug delivery system in Alzheimer's disease, demonstrating strong labeling of Aβ deposits both in human tissue and in mice, and in vitro downregulation of amyloid peptide secretion and prevention of Aβ-induced toxicity.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Autopsy; Coloring Agents; Curcumin; Humans; Liposomes; Mice; Nanoparticles; Neocortex; Peptide Fragments

The therapeutic effects of curcumin in treating Alzheimer's disease (AD) depend on the ability to penetrate the blood-brain barrier. The latest nanoparticle technology can help to improve the bioavailability of curcumin, which is affected by the final particle size and stability. We developed a stable curcumin nanoparticle formulation to test in vitro and in AD model Tg2576 mice. Flash nanoprecipitation of curcumin, polyethylene glycol-polylactic acid co-block polymer, and polyvinylpyrrolidone in a multi-inlet vortex mixer, followed by freeze drying with β-cyclodextrin, produced dry nanocurcumin with mean particle size <80 nm. Nanocurcumin powder, unformulated curcumin, or placebo was orally administered to Tg2576 mice for 3 months. Before and after treatment, memory was measured by radial arm maze and contextual fear conditioning tests. Nanocurcumin produced significantly (p=0.04) better cue memory in the contextual fear conditioning test than placebo and tendencies toward better working memory in the radial arm maze test than ordinary curcumin (p=0.14) or placebo (p=0.12). Amyloid plaque density, pharmacokinetics, and Madin-Darby canine kidney cell monolayer penetration were measured to further understand in vivo and in vitro mechanisms. Nanocurcumin produced significantly higher curcumin concentration in plasma and six times higher area under the curve and mean residence time in brain than ordinary curcumin. The P(app) of curcumin and tetrahydrocurcumin were 1.8×10(-6) and 1.6×10(-5)cm/s, respectively, for nanocurcumin. Our novel nanocurcumin formulation produced highly stabilized nanoparticles with positive treatment effects in Tg2576 mice.

Topics: Administration, Oral; Alzheimer Disease; Animals; Behavior, Animal; beta-Cyclodextrins; Blood-Brain Barrier; Brain; Chemistry, Pharmaceutical; Conditioning, Psychological; Curcumin; Disease Models, Animal; Dogs; Drug Stability; Fear; Female; Lactates; Madin Darby Canine Kidney Cells; Male; Maze Learning; Memory; Mice; Mice, Transgenic; Nanoparticles; Nanotechnology; Nootropic Agents; Particle Size; Permeability; Plaque, Amyloid; Polyethylene Glycols; Povidone; Technology, Pharmaceutical

Curcumin, an agent traditionally utilized for its preventative action against tumorigenesis, oxidation, inflammation, apoptosis and hyperlipemia, has also been used in the treatment of Alzheimer's disease (AD). Recent advances in the study of AD have revealed astrocytes (AS) as being key factors in the early pathophysiological changes in AD. Glial fibrillary acidic protein (GFAP), a marker specific to AS, is markedly more manifest during morphological modifications and neural degeneration signature during the onset of AD. Several studies investigating the functionality of curcumin have shown that it not only inhibits amyloid sedimentation but also accelerates the disaggregation of amyloid plaque. Thus, we are interested in the relationship between curcumin and spatial memory in AD. In this study, we intend to investigate the effects of curcumin in amyloid-β (Aβ(1-40)) induced AD rat models on both the behavioral and molecular levels, that is to say, on their spatial memory and on the expression of GFAP in their hippocampi. Our results were statistically significant, showing that the spatial memory of AD rats improved following curcumin treatment (p < 0.05), and that the expression of GFAP mRNA and the number of GFAP positive cells in the curcumin treated rats was decreased relative to the AD group rats (p < 0.05). Furthermore, the expression level of GFAP mRNA in hippocampal AS in the AD rats significantly increased when compared with that in the sham control (p < 0.05). Taken together, these results suggest that curcumin improves the spatial memory disorders (such disorders being symptomatic of AD) in Aβ(1-40)-induced rats by down regulating GFAP expression and suppressing AS activity.

Topics: Alzheimer Disease; Animals; Astrocytes; Curcumin; Disease Models, Animal; Glial Fibrillary Acidic Protein; Hippocampus; Learning; Male; Memory; Rats; Rats, Sprague-Dawley

To investigate the neuroprotective mechanism of combination extract of Renshen (Panax Ginseng), Yinyanghuo (Herba Epimedii Brevicornus), Yuanzhi (Radix Palygalae) and Jianghuang (Rhizoma Curcumae Longae) (GEPT) in treating Alzheimer's disease on the target of glycogen synthase kinase 3beta (GSK-3beta).. Three-month-old APPV7171 transgenic mice were randomly divided into ten groups (n = 12 per group) and intragastrically administrated vehicle or medicines: APP group was given 0.5% CMC, donepezil group was given donepezil (APP + D group) (0.92 mg/kg(-1) x day(-1)), and GEPT groups were given small dose of GEPT (APP+Gs group) (0.075 g/ kg(-1) x day(-1)), medium dose (APP+Gm group) (0.15 g/ kg(-1) day(-1)), and large dose (APP+GI group) (0.30 g/ kg(-1) x day(-1)) for 4 or 8 months, respectively. Three-month-old C57BL/6J mice as vehicle controls (n=12) were given 0.5% CMC for 4 or 8 months as well. The GSK-3beta expression in the cortex of 7- and 11-month-old APPV7171 transgenic mice with and without GEPT or donepezil treatment and normal C57BL/6J mice were measured via Western blotting and Immunohistochemistry.. Immunohistochemistry analysis showed significant increase of GSK-3beta in the cerebral cortex of 7-month-old APP group (compare to control group P = 0.003), while the GSK-3beta expression of donepezil or GEPT group were all significantly decreased (Donepezil vs APP: P = 0.041; GI vs APP: P = 0.049; Gm vs APP: P = 0.029; Gh vs APP: P = 0.036). Western blot analysis showed similar results. The densitometric measures of GSK-3beta in APP mice increased significantly as compared with the control group (P = 0.008). And the GSK-3beta expression in donepezil and GEPT groups were all decreased. There was significant difference between Gh group or donepezil group and the control group (P = 0.05). Similar findings were shown in the 11-month-old mice in each group, except for greater decrease of GSK-3beta in the GEPT group.. GEPT can effectively decrease the level of GSK-3beta expression in the brain cortex of APPV7171 transgenic mice, and such effect is more significant in 11-month-old mice. This partially explains the neuroprotecting mechanism of GEPT in preventing and treating of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Cortex; Curcuma; Disease Models, Animal; Down-Regulation; Drugs, Chinese Herbal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Panax; Peptide Fragments; Rhizome

The binding of curcumin to senile plaques (SPs) and cerebral amyloid angiopathy (CAA) was examined in the aged brain of various animal species and a human patient with Alzheimer's disease (AD), together with its binding to neurofibrillary tangles (NFTs). Brain sections were immunostained with anti-amyloid β protein 1-42 (Aβ42) and anti-amyloid β protein 1-40 (Aβ40) antibodies. These sections were also stained with alkaline Congo red, periodic acid-methenamine silver (PAM), and curcumin (0.009% curcumin solution) with or without formic acid pretreatment. The sections from the AD brain were also immunostained for anti-paired helical filament-tau (PHF-tau), and were stained with Gallyas silver for NFTs. Some SPs in the AD, monkey, dog, bear, and amyloid precursor protein transgenic mouse (APP Tg-mouse) brains contained congophilic materials, and were intensely positive for curcumin. In addition, curcumin labeled some diffuse SPs negative for Congo red in the AD, monkey, bear, and APP Tg-mouse brains. In all animals, CAA was intensely positive for both Congo red and curcumin. The specific curcumin staining activity was lost by formic acid pretreatment. In the AD brain, NFTs positive for PHF-tau and Gallyas silver were moderately stained with curcumin. These findings indicate that curcumin specifically binds to the aggregated Aβ molecules in various animals, and further to phosphorylated tau protein, probably according to its conformational nature.

Topics: Aging; Alzheimer Disease; Animals; Birds; Brain; Cerebral Amyloid Angiopathy; Curcumin; Humans; Mammals; Neurofibrillary Tangles; Plaque, Amyloid; Protein Binding

Neurodegenerative diseases are associated with accumulation of modified proteins or peptides including amyloid-β (Aβ) in Alzheimer's disease (AD), and misfolded superoxide dismutase-1 (SOD-1) in amyotrophic lateral sclerosis (ALS). Clearance of Aβ or SOD-1 by the innate immune system may be important for controlling or preventing disease onset. Curcumins restore Aβ phagocytosis by peripheral blood mononuclear cells (PBMCs) from AD patients and Aβ clearance with upregulation of key genes including MGAT3, vitamin D receptor (VDR) and Toll-like receptors (TLRs). Certain curcumins inhibit inflammatory processes of PBMCs from ALS patients. We developed an in vitro system using human monocytes from patients and monocytic cell lines (i.e. U-937, THP-1) for evaluating curcuminoid potency of innate immune cell stimulation. Bisdemethoxycurcumin and certain analogs potentiated MGAT3,VDR and TLR gene expression 3- to 300-fold in U-937 cells. The effect of curcumins on inflammation in monocytes from patients with ALS was examined. Recursive medicinal chemistry was applied to identify compounds that stimulate the innate immune system for use in the clearance of Aβ in AD and the reversal of neuroinflammation and defective SOD-1 accumulation in ALS.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyotrophic Lateral Sclerosis; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Transformed; Cells, Cultured; Curcumin; Cytokines; Diarylheptanoids; Gene Expression Regulation; Humans; Monocytes; N-Acetylglucosaminyltransferases; Receptors, Calcitriol; RNA, Messenger; Superoxide Dismutase; Toll-Like Receptors

The pathology of Alzheimer's disease (AD) is characterized by the presence of extracellular deposits of misfolded and aggregated amyloid-β (Aβ) peptide and intraneuronal accumulation of tangles comprised of hyperphosphorylated Tau protein. For several years, the natural compound curcumin has been proposed to be a candidate for enhanced clearance of toxic Aβ amyloid. In this study we have studied the potency of feeding curcumin as a drug candidate to alleviate Aβ toxicity in transgenic Drosophila. The longevity as well as the locomotor activity of five different AD model genotypes, measured relative to a control line, showed up to 75% improved lifespan and activity for curcumin fed flies. In contrast to the majority of studies of curcumin effects on amyloid we did not observe any decrease in the amount of Aβ deposition following curcumin treatment. Conformation-dependent spectra from p-FTAA, a luminescent conjugated oligothiophene bound to Aβ deposits in different Drosophila genotypes over time, indicated accelerated pre-fibrillar to fibril conversion of Aβ(1-42) in curcumin treated flies. This finding was supported by in vitro fibrillation assays of recombinant Aβ(1-42). Our study shows that curcumin promotes amyloid fibril conversion by reducing the pre-fibrillar/oligomeric species of Aβ, resulting in a reduced neurotoxicity in Drosophila.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Curcumin; Drosophila; Genotype; Neurotoxicity Syndromes; Polymerization; Survival Rate; Treatment Outcome

The natural product curcumin has gained considerable attention in recent years for its multiple pharmacological activities, but more efforts are needed to understand how curcumin can have these pharmacological effects considering its low bioavailability. In addition, it is unclear how curcumin exerts inhibitory effects against numerous enzymes, especially those that cannot accommodate curcumin within recognized binding pockets. By analyzing the similarities between the biological activities of curcumin and its degradation products against diseases such as Alzheimer's disease and cancer, as well as the preferential inhibition of some enzymes by degradation products, it appears that the bioactive degradation products may contribute to the pharmacological effects of curcumin. This possibility should be given full attention when elucidating the pharmacology of this promising natural product for various diseases.

Topics: Alzheimer Disease; Animals; Curcumin; Humans; Neoplasms; Proteolysis

Alzheimer's disease is a growing concern in the modern world. As the currently available medications are not very promising, there is an increased need for the fabrication of newer drugs. Curcumin is a plant derived compound which has potential activities beneficial for the treatment of Alzheimer's disease. Anti-amyloid activity and anti-oxidant activity of curcumin is highly beneficial for the treatment of Alzheimer's disease. The insolubility of curcumin in water restricts its use to a great extend, which can be overcome by the synthesis of curcumin nanoparticles. In our work, we have successfully synthesized water-soluble PLGA coated- curcumin nanoparticles and characterized it using different techniques. As drug targeting to diseases of cerebral origin are difficult due to the stringency of blood-brain barrier, we have coupled the nanoparticle with Tet-1 peptide, which has the affinity to neurons and possess retrograde transportation properties. Our results suggest that curcumin encapsulated-PLGA nanoparticles are able to destroy amyloid aggregates, exhibit anti-oxidative property and are non-cytotoxic. The encapsulation of the curcumin in PLGA does not destroy its inherent properties and so, the PLGA-curcumin nanoparticles can be used as a drug with multiple functions in treating Alzheimer's disease proving it to be a potential therapeutic tool against this dreaded disease.

Topics: Alzheimer Disease; Amyloid; Animals; Antioxidants; Biological Transport; Cell Line, Tumor; Curcumin; Lactic Acid; Mice; Molecular Imaging; Nanoconjugates; Nanoparticles; Peptide Fragments; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Protein Multimerization; Protein Structure, Secondary

Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved inhibitor function by 6-7-fold over that measured for curcumin.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Blood-Brain Barrier; Cell Line; Curcumin; Enzyme Inhibitors; Humans; Protein Multimerization

The pathogenesis of Alzheimer's disease (AD) involves a key event which changes the morphology of amyloid-β 42 (Aβ)₄₂ peptide from its soluble monomeric form into the fibrillated aggregates in the brain. Aluminum ion, Al(III), is known to act as a pathological chaperone of the Aβ₄₂ in this process; curcumin, a natural phenolic compound, is considered capable of binding Al(III) and Aβ₄₂; nevertheless, little is known about the combined action of curcumin and Al(III) on the Aβ₄₂ fibrillation and neurotoxicity. Here, combinations of circular dichroism spectroscopy, thioflavin T fluorescence, atomic force microscopy, Bradford and MTT assays, it is demonstrated that although Al(III) can promote the Aβ₄₂ fibrillation dose-dependently, leading to the high neurotoxicity to PC12 cells, curcumin can inhibit the events. Besides, we found that curcumin is able not only to inhibit the formation of Al(III)-induced Aβ₄₂ fibrillation, but also to form the Al(III)-curcumin complexes which in turn can remold the preformed, mature, ordered Aβ₄₂ fibrils into the low toxic amorphous aggregates. These findings suggest that curcumin could block the binding of Al(III) with Aβ₄₂ and form the Al(III)-curcumin complexes, so as to inhibit the Al(III)-induced Aβ₄₂ fibrillation and neurotoxicity. The Al(III)-curcumin complexes are worth potentially developing as a therapy agent against the neurodegenerative disorders in the future.

Topics: Aluminum; Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzothiazoles; Circular Dichroism; Curcumin; Microscopy, Atomic Force; Neurotoxicity Syndromes; PC12 Cells; Peptide Fragments; Rats; Thiazoles

Topics: Alzheimer Disease; Animals; Curcumin; Humans; Neoplasms

Aβ oligomers are potential targets for the diagnosis and therapy of Alzheimer's disease (AD). On the other hand, the molecule curcumin has been shown to possess significant therapeutic potential in many areas. In this paper, we use all-atom explicit solvent molecular dynamics simulations to study the effect of curcumin on the stability of Aβ amyloid protein oligomers. We observed that curcumin decreases the β-sheet secondary structural content within the Aβ oligomers without reducing the contacts between the monomers. The breaking of the β-sheet is found to be preceded by a deformation of the β-sheet structure due to hydrophobic interaction from the nearby curcumin. Furthermore, the π-stacking interaction between curcumin (keto ring and enol ring) and the aromatic residues of Aβ, which exists throughout the simulations, has also contributed to the diminishing of the β-sheet structure. Our analysis of the underwrapped amide-carbonyl hydrogen bonds reveals several stable dehydrons of the oligomer, especially the dehydron pair 34L and 41I, which curcumin tends to hover over. We have examined the paths of curcumin on the Aβ proteins and determined the common routes where curcumin lingers as it traverses around the Aβ. In consequence, our study has provided a detailed interaction picture between curcumin and the Aβ oligomers.

Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid beta-Peptides; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Curcumin; Humans; Molecular Dynamics Simulation; Molecular Sequence Data; Protein Multimerization; Protein Structure, Secondary

The extracellular senile plaques observed in Alzheimer's disease (AD) patients are mainly composed of amyloid peptides produced from the β-amyloid precursor protein (βAPP) by β- and γ-secretases. A third non-amyloidogenic α-secretase activity performed by the disintegrins ADAM10 and ADAM17 occurs in the middle of the amyloid-β peptide Aβ and liberates the large sAPPα neuroprotective fragment. Since the activation of α-secretase recently emerged as a promising therapeutic approach to treat AD, the identification of natural compounds able to trigger this cleavage is highly required. Here we describe new curcumin-based modified compounds as α-secretase activators. We established that the aminoacid conjugates curcumin-isoleucine, curcumin-phenylalanine and curcumin-valine promote the constitutive α-secretase activity and increase ADAM10 immunoreactivity. Strickingly, experiments carried out under conditions mimicking the PKC/muscarinic receptor-regulated pathway display different patterns of activation by these compounds. Altogether, our data identified new lead natural compounds for the future development of powerful and stable α-secretase activators and established that some of these molecules are able to discriminate between the constitutive and regulated α-secretase pathways.

Topics: ADAM Proteins; ADAM10 Protein; Alzheimer Disease; Amyloid Precursor Protein Secretases; Curcumin; Enzyme Activation; HEK293 Cells; Humans; Isoleucine; Membrane Proteins; Phenylalanine; Valine

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid β (Aβ) peptides and the failure of mechanisms to clear toxic aggregates. The Aβ42 peptide is considered to be a causative factor that underlies the pathophysiology of AD, in part due to its propensity for misfolding and aggregation; the small oligomers that result represent toxic species. Thus agents that prevent Aβ42 misfolding/aggregation or, alternatively improve Aβ42 oligomer clearance, may have significant therapeutic value. We have developed the basis for a drug screening system based on transgenic plant cells that express Aβ42 fusion proteins to serve as the reliable indicators of the general conformational status of Aβ42. Within cells of transgenic tobacco and Nicotiana benthamiana, misfolding of Aβ42 causes the misfolding of a GFP fusion partner, and consequently there is a loss of fluorescence associated with the native GFP protein. In a similar fusion consisting of Aβ42 linked to hygromycin phosphotransferase II (Hpt II), a hygromycin-resistance marker, misfolding of Aβ42 leads to a misfolded Hpt II, and consequently the transgenic cells are unable to grow on media containing hygromycin. Importantly, substitution of the 'aggregation-prone' Aβ42 with a missense mutant of Aβ42 (F19S/L34F) that is not prone to misfolding/aggregation, 'rescues' both fusion partners. Several 'positive control' chemicals that represent inhibitors of Aβ42 aggregation, including curcumin, epigallocatechin-3-gallate (EGCG), and resveratrol show efficacy in preventing the Aβ42-fusion proteins from misfolding/aggregating in the transgenic plant cells. We discuss the potential of the two fusion protein systems to serve as the basis for an inexpensive, selective, and efficient screening system in which a plant cell can fluoresce or survive only in the presence of drug candidates that are able to prevent Aβ42 misfolding/aggregation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Catechin; Cell Engineering; Curcumin; Drug Evaluation, Preclinical; Gene Expression; Genes, Reporter; Green Fluorescent Proteins; Humans; Microscopy, Fluorescence; Models, Biological; Mutation; Nicotiana; Peptide Fragments; Phosphotransferases (Alcohol Group Acceptor); Plant Cells; Protein Binding; Protein Conformation; Protein Folding; Recombinant Fusion Proteins; Resveratrol; Stilbenes

Combined results of theoretical molecular dynamic simulations and in vitro spectroscopic (circular dichroism and fluorescence) studies are presented, providing the atomistic and secondary structure details of the process by which a selected small molecule may destabilize the β-sheet ordered "amyloid" oligomers formed by the model undecapeptide of amyloid β-peptide 25-35 [Aβ(25-35)]. Aβ(25-35) was chosen because it is the shortest fragment capable of forming large β-sheet fibrils and retaining the toxicity of the full length Aβ(1-40/42) peptides. The conformational transition, that leads to the formation of β-sheet fibrils from soluble unordered structures, was found to depend on the environmental conditions, whereas the presence of myricetin destabilizes the self-assembly and antagonizes this conformational shift. In parallel, we analyzed several molecular dynamics trajectories describing the evolution of five monomer fragments, without inhibitor as well as in the presence of myricetin. Other well-known inhibitors (curcumin and (-)-tetracycline), found to be stronger and weaker Aβ(1-42) aggregation inhibitors, respectively, were also studied. The combined in vitro and theoretical studies of the Aβ(25-35) self-assembly and its inhibition contribute to understanding the mechanism of action of well-known inhibitors and the peptide amino acid residues involved in the interaction leading to a rational drug design of more potent new molecules able to antagonize the self-assembly process.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Circular Dichroism; Curcumin; Flavonoids; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Models, Molecular; Peptide Fragments; Protein Structure, Secondary; Spectrometry, Fluorescence; Temperature; Tetracycline

This study aims to determine the effects of curcumin and demethoxycurcumin on the internal ribosome entry site of the amyloid-β precursor protein (APP) and tau protein through a bi-cistronic reporter assay for screening of anti-Alzheimer's disease agents.. A bi-cistronic assay was performed wherein the expression of the first cistron, a β-galactosidase gene under the control of a cytomegalovirus promoter, represents the canonical cap-dependent mechanism of translation initiation; while the second cistron involves the utilization of the APP or the tau IRES elements to drive the expression of secreted alkaline phosphatase (SEAP) under a cap-independent mechanism. Bioactive natural products reported to have therapeutic potential for AD such as curcumin and demethoxycurcumin were screened in an murine neuroblastoma (N2A) cell model. Western blot analyses for the expression of APP C-terminal protein, human tau-1, and phosphorylated tau at Serine 262 (p(262)) and Serine 396 (pS(396)) were done after treatment of N2A cells with the test compounds.. The bi-cistronic reporter assay revealed that curcumin was more effective than demethoxycurcumin, a structural analog of curcumin, in inhibiting both APP and tau IRES-dependent translation initiation. This result was further confirmed by Western blot analysis for the expression of APP C-terminal protein, human tau-1, pS(262) and pS(396) suggesting that curcumin may play a role in AD pathology alleviation through the inhibition of the APP and tau IRES-mediated translation mechanism. On the other hand, demethoxycurcumin was observed to inhibit the phosphorylation of both tau pS(262) and pS(396).. A novel assay system using the bi-cistronic reporter constructs for the identification of compounds with activity against the translation directed by APP and tau IRES was developed. The results provide novel suggestive insights for the potential use of the mentioned compounds as prophylactic and therapeutic anti-AD agents.

Topics: Alkaline Phosphatase; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antioxidants; beta-Galactosidase; Cell Line, Tumor; Curcumin; Diarylheptanoids; Gene Expression; Genes, Reporter; Mice; Peptide Chain Initiation, Translational; Phosphorylation; Ribosomes; tau Proteins

In a previous in vitro study, the standardized turmeric extract, HSS-888, showed strong inhibition of Aβ aggregation and secretion in vitro, indicating that HSS-888 might be therapeutically important. Therefore, in the present study, HSS-888 was evaluated in vivo using transgenic 'Alzheimer' mice (Tg2576) over-expressing Aβ protein. Following a six-month prevention period where mice received extract HSS-888 (5mg/mouse/day), tetrahydrocurcumin (THC) or a control through ingestion of customized animal feed pellets (0.1% w/w treatment), HSS-888 significantly reduced brain levels of soluble (∼40%) and insoluble (∼20%) Aβ as well as phosphorylated Tau protein (∼80%). In addition, primary cultures of microglia from these mice showed increased expression of the cytokines IL-4 and IL-2. In contrast, THC treatment only weakly reduced phosphorylated Tau protein and failed to significantly alter plaque burden and cytokine expression. The findings reveal that the optimized turmeric extract HSS-888 represents an important step in botanical based therapies for Alzheimer's disease by inhibiting or improving plaque burden, Tau phosphorylation, and microglial inflammation leading to neuronal toxicity.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidosis; Analysis of Variance; Animals; Antioxidants; Curcuma; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Humans; Mice; Mice, Transgenic; Mutation; Peptide Fragments; Phosphorylation; Plant Extracts; tau Proteins

Alzheimer's disease (AD) involves multiple pathological processes in the brain, including increased inflammation and oxidative damage, as well as the accumulation of amyloid-β (Aβ) plaques. We hypothesized that a combinatorial therapeutic approach to target these multiple pathways may provide cognitive and neuropathological benefits for AD patients. To test this hypothesis, we used a canine model of human aging and AD. Aged dogs naturally develop learning and memory impairments, human-type Aβ deposits, and oxidative damage in the brain. Thus, 9 aged beagles (98-115 months) were treated with a medical food cocktail containing (1) an extract of turmeric containing 95% curcuminoids; (2) an extract of green tea containing 50% epigallocatechingallate; (3) N-acetyl cysteine; (4) R-alpha lipoic acid; and (5) an extract of black pepper containing 95% piperine. Nine similarly aged dogs served as placebo-treated controls. After 3 months of treatment, 13 dogs completed a variable distance landmark task used as a measure of spatial attention. As compared to placebo-treated animals, dogs receiving the medical food cocktail had significantly lower error scores (t11 = 4.3, p = 0.001) and were more accurate across all distances (F(1,9) = 20.7, p = 0.001), suggesting an overall improvement in spatial attention. Measures of visual discrimination learning, executive function and spatial memory, and levels of brain and cerebrospinal fluid Aβ were unaffected by the cocktail. Our results indicate that this medical food cocktail may be beneficial for improving spatial attention and motivation deficits associated with impaired cognition in aging and AD.

Topics: Aging; Alzheimer Disease; Animals; Antioxidants; Attention; Camellia sinensis; Curcuma; Disease Models, Animal; Dogs; Drug Therapy, Combination; Humans; Plant Extracts; Spatial Behavior

Noninvasive monitoring of β-amyloid (Aβ) plaques, the neuropathological hallmarks of Alzheimer's disease (AD), is critical for AD diagnosis and prognosis. Current visualization of Aβ plaques in brains of live patients and animal models is limited in specificity and resolution. The retina as an extension of the brain presents an appealing target for a live, noninvasive optical imaging of AD if disease pathology is manifested there. We identified retinal Aβ plaques in postmortem eyes from AD patients (n=8) and in suspected early stage cases (n=5), consistent with brain pathology and clinical reports; plaques were undetectable in age-matched non-AD individuals (n=5). In APP(SWE)/PS1(∆E9) transgenic mice (AD-Tg; n=18) but not in non-Tg wt mice (n=10), retinal Aβ plaques were detected following systemic administration of curcumin, a safe plaque-labeling fluorochrome. Moreover, retinal plaques were detectable earlier than in the brain and accumulated with disease progression. An immune-based therapy effective in reducing brain plaques, significantly reduced retinal Aβ plaque burden in immunized versus non-immunized AD mice (n=4 mice per group). In live AD-Tg mice (n=24), systemic administration of curcumin allowed noninvasive optical imaging of retinal Aβ plaques in vivo with high resolution and specificity; plaques were undetectable in non-Tg wt mice (n=11). Our discovery of Aβ specific plaques in retinas from AD patients, and the ability to noninvasively detect individual retinal plaques in live AD mice establish the basis for developing high-resolution optical imaging for early AD diagnosis, prognosis assessment and response to therapies.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Animals; Coloring Agents; Curcumin; Disease Models, Animal; Female; Humans; Imaging, Three-Dimensional; Immunohistochemistry; Male; Mice; Mice, Transgenic; Microscopy, Fluorescence; Middle Aged; Plaque, Amyloid; Retina; Spectrometry, Fluorescence

Alzheimer's disease and osteoporosis are often observed to co-occur in clinical practice. The present study aimed to evaluate the bone microarchitecture and bone mineral density (BMD) of the proximal tibia in APP/PS1 transgenic mice by micro-computed tomography (micro-CT), and to search for evidence that curcumin can be used to reduce bone mineral losses and treat osteoporosis after senile dementia in these transgenic mice. Three-month-old female mice were divided into the following groups (n=9 per group): wild-type mice (WT group); APP/PS1 transgenic mice (APP group); and APP/PS1 transgenic mice with curcumin treatment (APP+Cur group). Between 9 and 12 months of age, the APP+Cur group were administered curcumin orally (600ppm). CT scans of the proximal tibia were taken at 6, 9 and 12 months. At 6 months, there were little differences in the structural parameters. At 9 months, the APP groups displayed loss of bone volume ratio (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and connectivity density (Conn.D) and increases in trabecular separation (Tb.Sp) and geometric degree of anisotropy (DA) (P<0.05 or P<0.01), with significant changes in the BMD parameters. At 12 months, curcumin treatment led to constant increases in the trabecular bone mass of the metaphysis and clearly improved the BMD. By the same time, we measured the TNF-α and IL-6 in the serum among the different groups at 6, 9 and 12 months by enzyme-linked immunoassay(ELISA). These results suggest that APP/PS1 transgenic mice are susceptible to osteoporosis, and that curcumin can prevent further deterioration of the bone structure and produce beneficial changes in bone turnover. The change of inflammation cytokine, including TNF-α and IL-6, may play an important role in the mechanisms of action of curcumin, but the detail mechanism remains unknown.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Bone and Bones; Bone Density; Curcuma; Curcumin; Female; Interleukin-6; Mice; Mice, Inbred Strains; Mice, Transgenic; Osteoporosis; Phytotherapy; Plant Extracts; Tibia; Tomography, X-Ray Computed; Tumor Necrosis Factor-alpha

Widespread neuroinflammation in the central nervous system (CNS) of Alzheimer's disease (AD) patients, involving pro-inflammatory mediators such as complement components, might be responsible for AD associated behavioral symptoms such as anxiety. Vaccinia virus complement control protein (VCP) and curcumin (Cur) are the bioactive compounds of natural origin shown to inhibit the in-vitro complement activation. In order to develop complement regulatory compounds which could be delivered to the CNS by a non-invasive route, VCP, its truncated version (tVCP), and Cur were administered to Wistar rats intranasally. The distribution of these compounds in cerebrospinal fluid (CSF) was studied using an enzyme linked immunosorbent assay (ELISA), using VCP and tVCP as antigens and a modified fluorimetric method (Cur). VCP and tVCP were also detected in the olfactory lobes of the rat brain using immunohistochemical analysis. These compounds were then compared for their ability to attenuate the anxiety levels in APPswePS1δE9 mice using an elevated plus maze (EPM) apparatus. VCP treatment significantly improved the exploratory behavior and reduced the anxiety behavior in APPswePS1δE9 mice. tVCP however showed an opposite effect to VCP, whereas Cur showed no effect on the anxiety behavior of these mice. When these mice were subsequently tested for their cognitive performance in the Morris water maze (MWM), they showed tendencies to collide with the periphery of the walls of MWM. This unusual activity was termed "kissperi" behavior. This newly defined index of anxiety was comparable to the anxiety profile of the VCP and tVCP treated groups on EPM. VCP can thus be delivered to the CNS effectively via intranasal route of administration to attenuate anxiety associated with AD.

Topics: Administration, Intranasal; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anxiety; Complement System Proteins; Curcumin; Disease Models, Animal; ELAV Proteins; Enzyme-Linked Immunosorbent Assay; Humans; Maze Learning; Mice; Mice, Transgenic; Presenilin-1; Rats; Viral Proteins

The synthesis and characterization of "2 + 1" complexes of the [M(CO)(3)](+) (M = Re, (99m)Tc) core with the β-diketones acetylacetone (complexes 2, 8) and curcumin (complexes 5, 10 and 6, 11) as bidentate OO ligands, and imidazole or isocyanocyclohexane as monodentate ligands is reported. The complexes were synthesized by reacting the [NEt(4)](2)[Re(CO)(3)Br(3)] precursor with the β-diketone to generate the intermediate aqua complex fac-Re(CO)(3)(OO)(H(2)O) that was isolated and characterized, followed by replacement of the labile water by the monodentate ligand. All complexes were characterized by mass spectrometry, NMR and IR spectroscopies, and elemental analysis. In the case of complex 2, bearing imidazole as the monodentate ligand, X-ray analysis was possible. The chemistry was successfully transferred at (99m)Tc tracer level. The curcumin complexes 5 and 6, as well as their intermediate aqua complex 4, that bear potential for radiopharmaceutical applications due to the wide spectrum of pharmacological activity of curcumin, were successfully tested for selective staining of β-amyloid plaques of Alzheimer's disease. The fact that the complexes maintain the affinity of the mother compound curcumin for β-amyloid plaques prompts for further exploration of their chemistry and biological properties as radioimaging probes.

Topics: Alzheimer Disease; Brain; Carbon Monoxide; Crystallography, X-Ray; Curcumin; Cyclohexanes; Humans; Imidazoles; Nitriles; Organometallic Compounds; Organotechnetium Compounds; Plaque, Amyloid; Radiopharmaceuticals; Rhenium; Technetium

A novel series of N,N'-bis-methylenedioxybenzyl-alkylenediamines 5a-5g have been designed, synthesized and evaluated as bivalent anti-Alzheimer's disease ligands. The enzyme inhibition assay results indicated that compounds 5e-5g inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the micromolar range (IC(50), 2.76-4.24 µM for AChE and 3.02-5.14 µM for BuChE), which was in the same potential as the reference compound rivastigmine (IC(50), 5.50 µM for AChE and 1.60 µM for BuChE). It was found that compounds could bind simultaneously to the peripheral and catalytic sites of AChE. β-Amyloid (Aβ) aggregation inhibition assay results showed that compound 5e exhibited highest self-mediated Aβ fibril aggregation inhibition activity (40.3%) with a similar potential as curcumin (41.6%). It was also found that 5e-5g did not affect neuroblastoma cell viability at the concentration of 50 μM.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzophenones; Cells, Cultured; Curcumin; Diamines; Enzyme Activation; Enzyme Inhibitors; Humans; Inhibitory Concentration 50; Ligands; Methylene Chloride

The aggregation of the amyloid-β-peptide (AβP) into well-ordered fibrils has been considered as the key pathological marker of Alzheimer's disease. Molecular attributes related to the specific binding interactions, covalently and non-covalently, of a library of compounds targeting of conformational scaffolds were computed employing static lattice atomistic simulations and array constructions. A combinatorial approach using isobolographic analysis was stochastically modeled employing Artificial Neural Networks and a Design of Experiments approach, namely an orthogonal Face-Centered Central Composite Design for small molecules, such as curcumin and glycosylated nornicotine exhibiting concentration-dependent behavior on modulating AβP aggregation and oligomerization. This work provides a mathematical and in silico approach that constitutes a new frontier in providing neuroscientists with a template for in vitro and in vivo experimentation. In future this could potentially allow neuroscientists to adopt this in silico approach for the development of novel therapeutic interventions in the neuroprotection and neurotherapy of Alzheimer's disease. In addition, the neuroprotective entities identified in this study may also be valuable in this regard.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Computational Biology; Curcumin; Humans; Neuroprotective Agents; Nicotine

Wnt/β-catenin signaling pathway plays an important role in the genesis and development of Alzheimer's disease. The study aims to investigate the effect of Curcumin on the expression of GSK-3β, β-catenin and CyclinD1 in vitro, which are tightly correlated with Wnt/β-catenin signaling pathway, and also to explore the mechanisms, which will provide a novel therapeutic intervention for treatment of Alzheimer's disease. Plasmid APPswe and BACE1-mychis were transiently co-transfected into SHSY5Y cells by Liposfectamin™2000. The cells were treated with Curcumin at 0, 1.25, 5.0, 20.0 μmol/L for 24 h, or with Curcumin at 5.0 μmol/L for 0, and 12, 24 and 48 h for time course assay. Cell lysates were collected for RT-PCR, Western blot assay and immunofluorescent staining were carried out for detecting the effect of Curcumin on the expression of GSK-3β, β-catenin and CyclinD1. RT-PCR and Western blot results showed that the expression of GSK-3β mRNA and protein significantly decreased in the transfected cells treated with Curcumin, and that the changes were in a dose and time-dependent manner (P<0.05); however, the protein expression of GSK-3β-Ser9 was increased (P<0.05). Meanwhile, the expressions of β-catenin and transcriptional factors CyclinD1 mRNA and protein increased and the changes were also in a dose and time-dependent manner (P<0.05). Immunofluorescent staining results not only confirmed the above changes, but also showed that β-catenin had translocated into the nucleus gradually with the increased dosage of Curcumin. Therefore, GSK-3β is a potential target for treatment of AD. Curcumin could activate the Wnt/β-catenin signaling pathway through inhibiting the expression of GSK-3β and inducing the expression of β-catenin and CyclinD1, which will provide a new theory for treatment of neurodegenerative diseases by Curcumin.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; beta Catenin; Blotting, Western; Cell Line, Tumor; Curcumin; Cyclin D1; Fluorescent Antibody Technique; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Microscopy, Confocal; Plasmids; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Wnt Proteins

Practical biomarkers of Alzheimer's disease (AD) prognosis are lacking. Correspondingly, no drugs are known to decrease disease progression, although vitamin D3 has positive effects on cognition in vivo and 1α, 25-dihydroxyvitamin D3 (1,25 D3) on amyloid-β 1-42 (Aβ) phagocytosis in vitro. We have examined in a pilot study a new biomarker in peripheral blood mononuclear cells, the transcription of mRNA of β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase (MGAT3), the essential gene for Aβ phagocytosis. The transcription of MGAT3 stimulated by Aβ distinguishes macrophages into Type 0 (very low MGAT3 transcription), Type I (low MGAT3 transcription up regulated by bisdemethoxycurcumin), and Type II (high MGAT3 transcription down regulated by bisdemethoxycurcumin). In this pilot study of 20 AD patients and 20 control subjects, 45% patients, but only 10% control subjects, were Type 0 (p-value = 0.009). Type 0 AD patients had worse 2-year prognosis regarding loss of independence than Type I and Type II patients (p-value = 0.013). Phagocytosis of Aβ in Type I and II patients was shown to be dependent on 1,25 D3 using a specific inhibitor of the 1,25 D3-VDR activated nuclear receptor transcription factor. In a Type II patient, recovery from cognitive dysfunction related to surgical anesthesia was preceded by an improvement in phagocytosis of Aβ. The results of this pilot study suggest that the MGAT3 Type biomarker may characterize subgroups of AD patients with different disease progression. In vitro results suggest that vitamin D3 supplementation might be beneficial in both Type I and II patients, whereas curcuminoids only in Type I. These results must be investigated in a large prospective study.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Cells, Cultured; Curcumin; Female; Humans; Male; N-Acetylglucosaminyltransferases; Pilot Projects; Prognosis; RNA, Messenger; Vitamin D

Amyloid β (Aβ) deposition in the brain is considered the initiating event in the progression of Alzheimer's disease (AD). Amyloid imaging is widely studied in diagnosing AD and evaluating the disease stage, with considerable advances achieved in recent years. We have developed a novel ¹⁹F-containing curcumin derivative (named FMeC1) as a potential imaging agent. This compound can exist in equilibrium between keto and enol tautomers, with the enol form able to bind Aβ aggregates while the keto form cannot. This study investigated whether FMeC1 is suitable as a ¹⁹F magnetic resonance imaging (MRI) probe to detect Aβ deposition in the Tg2576 mouse, a model of AD. In ¹⁹F nuclear magnetic resonance (NMR) spectra obtained from the whole head, a delayed decreased rate of F ¹⁹F signal was observed in Tg2576 mice that were peripherally injected with FMeC1 in comparison to wild-type mice. Furthermore, ¹⁹F MRI displayed remarkable levels of ¹⁹F signal in the brain of Tg2576 mice after the injection of FMeC1. Histological analysis of FMeC1-injected mouse brain showed penetration of the compound across the blood-brain barrier and binding to Aβ plaques in peripherally injected Tg2576 mice. Moreover, the distribution of Aβ deposits in Tg2576 mice was in accordance with the region of the brain in which the ¹⁹F signal was imaged. FMeC1 also exhibited an affinity for senile plaques in human brain sections. These findings suggest the usefulness of FMeC1 as a ¹⁹F MRI probe for the detection of amyloid deposition in the brain. Furthermore, the properties of FMeC1 could form the basis for further novel amyloid imaging probes.

Topics: Alzheimer Disease; Animals; Brain; Curcumin; Disease Models, Animal; Magnetic Resonance Spectroscopy; Mice; Mice, Transgenic; Plaque, Amyloid; Radionuclide Imaging

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders. Elevated copper (Cu) ions are thought to link AD pathology. Curcumin is suggested to treat AD because of its high anti-oxidative activity and coordination to transitional metal ions. In this study, the protective effect of curcumin against the Cu(II)-induced oxidative damage was investigated in primary rat cortical neurons. The neuronal damage was assessed by morphological observation, cell viability, and oxidative stress level. The results showed that curcumin at low dosage protected primary cultured neurons from the 20 μM Cu(II)-induced damage. Low dosage of curcumin depressed oxidative stress levels exacerbated by Cu(II). However, high dosage of curcumin failed to decrease the Cu(II)-induced oxidative stress. When Cu(II) was presented in primary neurons, curcumin at high dosage resulted in chromosomal aberration and cell damage. These results suggest that curcumin, in a concentration-dependent manner, plays both anti-oxidative and pro-oxidative roles in primary neurons treated with Cu(II).

Topics: Alzheimer Disease; Animals; Antioxidants; Cell Survival; Cells, Cultured; Cerebral Cortex; Copper; Curcumin; Disease Models, Animal; Dose-Response Relationship, Drug; Homeostasis; Neurons; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

Alzheimer's disease (AD) is a neurodegenerative disorder, which depicts features of chronic inflammatory conditions resulting in cellular death and has limited therapeutic options. We aimed to explore the effect of a curcuminoid mixture and its individual components on inflammatory and apoptotic genes expression in AD using an Aβ+ibotenic acid-infused rat model. After 5 days of treatment with demethoxycurcumin, hippocampal IL-1β levels were decreased to 118.54 ± 47.48 and 136.67 ± 31.96% respectively at 30 and 10mg/kg, compared with the amyloid treated group (373.99 ± 15.28%). After 5 days of treatment, the curcuminoid mixture and demethoxycurcumin effectively decreased GFAP levels in the hippocampus. When studied for their effect on apoptotic genes expression, the curcuminoid mixture and bisdemethoxycurcumin effectively decreased caspase-3 level in the hippocampus after 20 days of treatment, where bisdemethoxycurcumin showed a maximal rescuing effect (92.35 ± 3.07%) at 3mg/kg. The curcuminoid mixture at 30 mg/kg decreased hippocampal FasL level to 70.56 ± 3.36% after 5 days of treatment and 19.01 ± 2.03% after 20 days. In the case of Fas receptor levels, demethoxycurcumin decreased levels after 5 days of treatment with all three doses showing a maximal effect (189.76 ± 15.01%) at 10mg/kg. Each compound was effective after 20 days in reducing Fas receptor levels in the hippocampus. This study revealed the important effect of curcuminoids on genes expression, showing that, each component of the curcuminoid mixture distinctly affects gene expression, thus highlighting the therapeutic potential of curcuminoids in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Curcumin; Cyclooxygenase 2; Disease Models, Animal; Excitatory Amino Acid Agonists; Fas Ligand Protein; fas Receptor; Frontal Lobe; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hippocampus; Ibotenic Acid; Inflammation; Interleukin-1beta; Male; Peptide Fragments; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Time Factors

The effect of various types of nanoliposomes (associated with curcumin, phosphatidic acid, cardiolipin, or GM1 ganglioside) on the aggregation of the amyloid-β(1-42) (Aβ(1-42)) peptide was investigated. Nanoliposomes incorporating curcumin (curcumin-liposomes) were prepared by adding curcumin in the lipid phase during liposome preparation, whereas curcumin surface-decorated liposomes were prepared by using a curcumin-lipid conjugate (lipid-S-curcumin liposomes) or by attaching a curcumin derivative on preformed liposomes by click chemistry (click-curcumin liposomes). The lipid ligands (phosphatidic acid, cardiolipin, or GM1) were also incorporated into nanoliposomes during their formation. All nanoliposomes with curcumin, or the curcumin derivative, were able to inhibit the formation of fibrillar and/or oligomeric Aβ in vitro. Of the three forms of curcumin liposomes tested, the click-curcumin type was by far the most effective. Liposomes with lipid ligands only inhibited Aβ fibril and oligomer formation at a very high ratio of liposome to peptide. Curcumin-based liposomes could be further developed as a novel treatment for Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cardiolipins; Curcumin; G(M1) Ganglioside; Humans; Ligands; Liposomes; Nanoparticles; Peptide Fragments; Phosphatidic Acids

Curcumin derivatives with high chemical stability, improved solubility and carrying a functionalized appendage for the linkage to other entities, have been synthesized in a straightforward manner. All compounds retained Curcumin ability to bind Aβ peptide oligomers without inducing their aggregation. Moreover all Curcumin derivatives were able to stain very efficiently Aβ deposits.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain Chemistry; Curcumin; Histocytochemistry; Humans; Mice; Mice, Transgenic; Molecular Dynamics Simulation; Nuclear Magnetic Resonance, Biomolecular; Peptide Fragments; Protein Binding; Solubility

A series of novel curcumin analogues were designed, synthesized, and evaluated as potential multifunctional agents for the treatment of AD. The in vitro studies showed that these compounds had better inhibitory properties against Aβ aggregation than curcumin. Superior anti-oxidant properties (better than the reference compound Trolox) of these compounds were observed by the oxygen radical absorbance capacity (ORAC) method and a cell-based assay using DCFH-DA as a probe. In addition they were able to chelate metals such as iron and copper and decrease metal-induced Aβ aggregation. The structure-activity relationships were discussed. The results suggested that our curcumin analogues could be selected as multifunctional agents for further investigation of AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Cell Line, Tumor; Chelating Agents; Curcumin; Dose-Response Relationship, Drug; Drug Design; Humans; Molecular Structure; Peptide Fragments; Reactive Oxygen Species; Stereoisomerism; Structure-Activity Relationship

Alzheimer's disease is characterized by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. We previously developed [(18)F]fluoropropylcurcumin ([(18)F]FP-curcumin), which demonstrated excellent binding affinity (K(i)=0.07 nM) for Aβ(1-40) aggregates and good pharmacokinetics in normal mouse brains. However, its initial brain uptake was poor (0.52% ID/g at 2 min post-injection). Therefore, in the present study, fluorine-substituted 4,4'-bissubstituted or pegylated curcumin derivatives were synthesized and evaluated. Their binding affinities for Aβ(1-42) aggregates were measured and 1-(4-fluoroethyl)-7-(4'-methyl)curcumin (1) had the highest binding affinity (K(i)=2.12 nM). Fluorescence staining of Tg APP/PS-1 mouse brain sections demonstrated high and specific labeling of Aβ plaques by 1 in the cortex region, which was confirmed with thioflavin-S staining of the same spots in the adjacent brain sections. Radioligand [(18)F]1 was found to have an appropriate partition coefficient (logP(o/w)=2.40), and its tissue distribution in normal mice demonstrated improved brain permeability (1.44% ID/g at 2 min post-injection) compared to that of [(18)F]FP-curcumin by a factor of 2.8 and fast wash-out from mouse brains (0.45% ID/g at 30 min post-injection). These results suggest that [(18)F]1 may hold promise as a PET radioligand for Aβ plaque imaging.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Brain; Curcumin; Drug Evaluation, Preclinical; Fluorine Radioisotopes; Humans; Mice; Mice, Transgenic; Peptide Fragments; Permeability; Plaque, Amyloid; Radionuclide Imaging; Radiopharmaceuticals; Sensitivity and Specificity; Tissue Distribution

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cholecalciferol; Curcumin; Diarylheptanoids; Disease Progression; Humans; Leukocytes, Mononuclear; N-Acetylglucosaminyltransferases; Phagocytosis; Precision Medicine; Prognosis

Curcumin has been reported to inhibit the generation of Aβ, but the underlying mechanisms by which this occurs remain unknown. Aβ is thought to play an important role in the pathogenesis of Alzheimer's disease (AD). The amyloid hypothesis argues that aggregates of Aβ trigger a complex pathological cascade that leads to neurodegeneration. Aβ is generated by the processing of APP (amyloid precursor protein) by β- and γ-secretases. Presenilin 1 (PS1) is central to γ-secretase activity and is a substrate for GSK-3β, both of which are implicated in the pathogenesis of AD. The present study aimed to investigate the effects of curcumin on the generation of Aβ in cultured neuroblastoma cells and on the in vitro expression of PS1 and GSK-3β. To stimulate Aβ production, a plasmid expressing APP was transfected into human SH-SY5Y neuroblastoma cells. The transfected cells were then treated with curcumin at 0-20 μM for 24 h or with 5 μM curcumin for 0-48 h, and the extracellular levels of Aβ(40/42) were determined by ELISA. The levels of PS1 and GSK-3β mRNA were measured by RT-PCR, and the expression of the PS1 and GSK-3β proteins (including the phosphorylated form of GSK-3β, p-GSK-3β-Ser9) were evaluated by western blotting. Curcumin treatment was found to markedly reduce the production of Aβ(40/42). Treatment with curcumin also decreased both PS1 and GSK-3β mRNA and protein levels in a dose- and time-dependent manner. Furthermore, curcumin increased the inhibitory phosphorylation of GSK-3β protein at Ser9. Therefore, we propose that curcumin decreases Aβ production by inhibiting GSK-3β-mediated PS1 activation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Cell Line, Tumor; Curcumin; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Neuroblastoma; Phosphorylation; Presenilin-1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Cognition; Curcumin; Disease Models, Animal; Heat-Shock Proteins; Hippocampus; Humans; Immunohistochemistry; Inflammation; Long-Term Potentiation; Memory; Mice; Nerve Growth Factors; Neuroprotective Agents; Oxidants; Oxidative Stress; Phosphorylation; Pyrazoles; Rats; Solubility; Structure-Activity Relationship; Synapses; Up-Regulation

The synthesis of a water/plasma soluble, noncytotoxic, "clicked" sugar-derivative of curcumin with amplified bioefficacy in modulating amyloid-β and tau peptide aggregation is presented. Curcumin inhibits amyloid-β and tau peptide aggregation at micromolar concentrations; the sugar-curcumin conjugate inhibits Aβ and tau peptide aggregation at concentrations as low as 8 nM and 0.1 nM, respectively. In comparison to curcumin, this conveniently synthesized Alzheimer's drug candidate is a more powerful antioxidant.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Cells, Cultured; Curcumin; Galactose; Hippocampus; Humans; Mice; tau Proteins

Curcumin, which can exist in an equilibrium between keto and enol tautomers, binds to beta-amyloid (Abeta) fibrils/aggregates. The aim of this study was to assess the relationship between the tautomeric structures of curcumin derivatives and their Abeta-binding activities. Curcumin derivatives with keto-enol tautomerism showed high levels of binding to Abeta aggregates but not to Abeta monomers. The binding activity of the keto form analogue of curcumin to Abeta aggregates was found to be much weaker than that of curcumin derivatives with keto-enol tautomerism. The color of a curcumin derivative with keto-enol tautomerism, which was substituted at the C-4 position, changed from yellow to orange within 30 min of being combined with Abeta aggregates in physiological buffer. This resulted from a remarkable increase in the enol form with extended conjugation of double bonds upon binding. These findings suggest that curcumin derivatives exist predominantly in the enol form during binding to Abeta aggregates, and that the enolization of curcumin derivatives is crucial for binding to Abeta aggregates. The keto-enol tautomerism of curcumin derivatives may be a novel target for the design of amyloid-binding agents that can be used both for therapy and for amyloid detection in Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Curcumin; Magnetic Resonance Spectroscopy; Methanol; Protein Binding; Protein Structure, Quaternary; Solutions; Spectrophotometry, Ultraviolet; Stereoisomerism

Beta amyloid plays a main role in the pathophysiology of Alzheimer's disease by inducing oxidative stress in the brain. Curcumin, a natural antioxidant, is known to inhibit beta amyloid and beta amyloid induced oxidative stress. However, low bioavailability and photodegradation are the major concerns for the use of curcumin. In the present study, we have formulated apolipoprotein E3 mediated poly(butyl) cyanoacrylate nanoparticles containing curcumin (ApoE3-C-PBCA) to provide photostability and enhanced cell uptake of curcumin by targeting. Prepared nanoparticles were characterized for particle size, zeta potential, entrapment efficiency and in vitro drug release. The entrapment of curcumin inside the nanoparticles was confirmed by X-ray diffraction analysis. Physicochemical characterization confirmed the suitability of the method of preparation. The photostability of curcumin was increased significantly in nanoparticles compared to plain curcumin. In vitro cell culture study showed enhanced therapeutic efficacy of ApoE3-C-PBCA against beta amyloid induced cytotoxicity in SH-SY5Y neuroblastoma cells compared to plain curcumin solution. Beta amyloid is known to induce apoptosis in neuronal cells, therefore antiapoptotic activity of curcumin was studied using flow cytometry assays. From all the experiments, it was found that the activity of curcumin was enhanced with ApoE3-C-PBCA compared to plain curcumin solution suggesting enhanced cell uptake and a sustained drug release effect. The synergistic effect of ApoE3 and curcumin was also studied, since ApoE3 also possesses both antioxidant and antiamyloidogenic activity. It was found that ApoE3 did indeed have activity against beta amyloid induced cytotoxicity along with curcumin. Hence, ApoE3-C-PBCA offers great advantage in the treatment of beta amyloid induced cytotoxicity in Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E3; Apoptosis; Caspase 3; Cell Cycle; Cell Line, Tumor; Curcumin; Enbucrilate; Flow Cytometry; Humans; Models, Theoretical; Nanoparticles; Polymers; Reactive Oxygen Species; X-Ray Diffraction

The transgenic mouse Tg2576 is widely used as a murine model of Alzheimer's disease (AD) and exhibits plaque pathogenesis in the brain and progressive memory impairments. Here we report that Tg2576 mice also have severe spinal cord deficits. At 10 months of age, Tg2576 mice showed a severe defect in the hindlimb extension reflex test and abnormal body trembling and hindlimb tremors when suspended by the tail. The frequency and severity of these abnormalities were overt at 10 months of age and became gradually worsened. On the foot-printing analysis, Tg2576 mice had shorter and narrower strides than the non-transgenic control. Histological analyses showed that neuronal cells including cholinergic neurons in the lumbar cord of Tg2576 mice were severely reduced in number. At 16 months of age, Tg2576 mice showed high levels of amyloid-beta accumulation in the spinal cord. Consistent with this, Tg2576 mice showed that lipid peroxidation levels were increased and mitochondrial metabolic activity were significantly reduced in the spinal cord. Administration of curcumin, a natural compound that has antioxidant properties, notably reversed motor function deficits of Tg2576 mice. The enhanced lipid peroxidation and neuronal loss in the lumbar cord was also partially suppressed by curcumin. Electron microscopic analysis revealed that the sciatic nerve fibers were severely reduced in number and were demyelinated in Tg2576 mice, which were partially rescued by curcumin. These results showed that Tg2576 mice display severe degeneration of motor neurons in the spinal cord and associated motor function deficits.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cholinergic Agents; Curcumin; Disease Models, Animal; Hindlimb; Humans; Lipid Peroxidation; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Mitochondria; Motor Neurons; Movement Disorders; Nerve Degeneration; Potassium Cyanide; Reflex; Spinal Cord; Tremor

The study aimed to characterize curcumin (CCM) (fluorescent yellow curry pigment) labeling of neuronal fibrillar tau inclusions (FTIs) in representative cases of 3 main tauopathies: Alzheimer disease (AD), progressive supranuclear palsy, and Pick disease. After identification of FTIs in hematoxylin and eosin-stained brain sections, sequential labeling and signal colocalization image analysis were used to compare CCM with thioflavine S (ThS), monoclonal antibody AT8 immunofluorescence, and Gallyas silver staining by visualizing the same FTIs. Curcumin preference for specific tau isoforms was tested with 3-repeat tau and 4-repeat tau isoform-specific immunofluorescence. Curcumin proved highly comparable to ThS and Gallyas staining in its detection of FTIs. When comparing CCM with AT8, ThS, and Gallyas staining in AD and progressive supranuclear palsy, 3 types of neuronal tau deposits were observed: nonfibrillar intracellular material labeled only with AT8, fibrillar intracellular inclusions labeled by all the methods, and fibrillar extracellular FTIs labeled with CCM, ThS, and Gallyas staining but not with AT8. Although CCM labeling overlapped with both 3-repeat tau and 4-repeat tau in AD, it did not label 3-repeat tau FTIs in Pick disease probably because of their different ultrastructural characteristics. In summary, CCM fluorescence reliably detected neuronal FTIs in AD and progressive supranuclear palsy and surpassed AT8 immunolabeling in visualizing later stages of FTIs, including ghost tangles. These results provide the basis for potential future applications of CCM binding of tau aggregates in diagnostic pathology and in vivo.

Topics: Alzheimer Disease; Benzothiazoles; Brain Diseases; Curcumin; Humans; Neurofibrillary Tangles; Neurons; Pick Disease of the Brain; Silver Staining; Supranuclear Palsy, Progressive; tau Proteins; Tauopathies; Thiazoles

Alzheimer's disease (AD) is a neurodegenerative disease. There are a limited number of therapeutic options available for the treatment of AD. Curcuminoids (a mixture of bisdemethoxycurcumin, demethoxycurcumin and curcumin) is the main chemical constituent found in turmeric, a well known curry spice, having potential in the treatment of AD. The objective of this study was to investigate the effects of curcuminoid mixture and individual constituents on spatial learning and memory in an amyloid-beta (Abeta) peptide-infused rat model of AD and on the expression of PSD-95, synaptophysin and camkIV. Curcuminoid mixture showed a memory-enhancing effect in rats displaying AD-like neuronal loss only at 30 mg/kg, whereas individual components were effective at 3-30 mg/kg. A shorter duration treatment with test compounds showed that the curcuminoid mixture and bisdemethoxycurcumin increased PSD-95 expression in the hippocampus at 3-30 mg/kg, with maximum effect at a lower dose (3 mg/kg) with respective values of 470.5 and 587.9%. However, after a longer duration treatment, two other compounds (demethoxycurcumin and curcumin) also increased PSD-95 to 331.7 and 226.2% respectively at 30 mg/kg. When studied for their effect on synaptophysin in the hippocampus after the longer duration treatment, the curcuminoid mixture and all three individual constituents increased synaptophysin expression. Of these, demethoxycurcumin was the most effective showing a 350.1% increase (P<0.01) at 30 mg/kg compared to the neurotoxin group. When studied for their effect on camkIV expression after longer treatment in the hippocampus, only demethoxycurcumin at 30 mg/kg increased levels to 421.2%. These compounds salvaged PSD-95, synaptophysin and camkIV expression levels in the hippocampus in the rat AD model, which suggests multiple target sites with the potential of curcuminoids in spatial memory enhancing and disease modifying in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 4; Cell Count; Curcumin; Diarylheptanoids; Disks Large Homolog 4 Protein; Gene Expression Profiling; Hippocampus; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Memory; Neuronal Plasticity; Neurons; Peptide Fragments; Rats; Rats, Sprague-Dawley; Synaptophysin; Time Factors

The hallmark of Alzheimer's disease (AD) is the accumulation of β-amyloid protein (Aβ). Aβ is generated from the β-amyloid precursor protein (APP) through the proteolysis of β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Aβ(42) isoform is more easily aggregate and more toxic to neurons than any other Aβ isoforms, thus being regarded as the primary toxic specie in AD. Curcumin mix has potent anti-amyloidogenic effect and shows great promise for AD treatment and prevention. The present study was conducted to examine the effects of curcumin mix and its different curcuminoids including curcumin (Cur), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) on Aβ(42), APP and BACE1. We found that Cur was the most active curcuminoid fraction in suppressing Aβ(42) production and the order of inhibitory potency of other curcuminoids was DMC>curcumin mix>BDMC. Cur, but not other curcuminoids, could reduce APP protein expression and none of curcuminoids affected APP mRNA level. BDMC could reduce BACE1 mRNA and protein levels, while DMC only affected BACE1 mRNA expression. Our data indicate that the anti-amyloidogenic effect of Cur may be mediated through the modulation of APP, while the anti-amyloidogenic effect of BDMC may be mediated through the modulation of BACE1.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Cell Survival; Curcumin; Diarylheptanoids; HEK293 Cells; Humans; Mutation; Peptide Fragments

Herein we report that Aβ aggregates, not Aβ monomer, can convert Z-DNA back to B-form, and curcumin, a well-known Aβ aggregation inhibitor, can stop DNA Z-B transition studied by means of biophysical and biochemical methods.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Curcumin; DNA, Z-Form; Enzyme Inhibitors; Humans; Models, Molecular; Protein Multimerization

Dietary supplements have been extensively studied for their beneficial effects on cognition and AD neuropathology. The current study examines the effect of a medical food cocktail consisting of the dietary supplements curcumin, piperine, epigallocatechin gallate, α-lipoic acid, N-acetylcysteine, B vitamins, vitamin C, and folate on cognitive functioning and the AD hallmark features and amyloid-beta (Aβ) in the Tg2576 mouse model of the disease.. The study found that administering the medical food cocktail for 6 months improved cortical- and hippocampal- dependent learning in the transgenic mice, rendering their performance indistinguishable from non-transgenic controls. Coinciding with this improvement in learning and memory, we found that treatment resulted in decreased soluble Aβ, including Aβ oligomers, previously found to be linked to cognitive functioning.. In conclusion, the current study demonstrates that combination diet consisting of natural dietary supplements improves cognitive functioning while decreasing AD neuropathology and may thus represent a safe, natural treatment for AD.

Topics: Acetylcysteine; Alkaloids; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Ascorbic Acid; Benzodioxoles; Brain; Catechin; Cerebral Cortex; Cognition; Curcumin; Dietary Supplements; Folic Acid; Hippocampus; Humans; Immunoblotting; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Piperidines; Polyunsaturated Alkamides; Thioctic Acid; Vitamin B Complex; Vitamins

Serotonin 5-HT(4) receptor (5-HT(4)R) agonists are of particular interest for the treatment of Alzheimer's disease because of their ability to ameliorate cognitive deficits and to modulate production of amyloid beta-protein (Abeta). However, despite the range of 5-HT(4)R agonists synthesized to date, potent and selective 5-HT(4)R agonists are still lacking. In the present study, two libraries of molecules based on the scaffold of ML10302, a highly specific and partial 5-HT(4)R agonist, were efficiently prepared by parallel supported synthesis and their binding affinities and agonist activities evaluated. Furthermore, we showed that, in vivo, the two best candidates exhibited neuroprotective activity by increasing the level of the soluble form of the amyloid precursor protein (sAPPalpha) in the cortex and hippocampus of mice. Interestingly, one of these compounds could also inhibit Abeta fibril formation in vitro.

Topics: Alzheimer Disease; Aminobenzoates; Amyloid; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Biopolymers; Cell Line, Tumor; Cerebral Cortex; Cyclic AMP; Drug Design; Hippocampus; Humans; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; para-Aminobenzoates; Peptide Fragments; Piperidines; Radioligand Assay; Rats; Serotonin 5-HT4 Receptor Agonists; Structure-Activity Relationship

Curcumin was investigated as an inhibitor of glycogen synthase kinase-3beta (GSK-3beta) in an attempt to explain some of its interesting multiple pharmacological effects, such as its anti-diabetic, anti-inflammatory, anti-cancer, anti-malarial and anti-alzheimer's properties. The investigation included simulated docking experiments to fit curcumin within the binding pocket of GSK-3beta followed by experimental in vitro and in vivo validations. Curcumin was found to optimally fit within the binding pocket of GSK-3beta via several attractive interactions with key amino acids. Experimentally, curcumin was found to potently inhibit GSK-3beta (IC50 = 66.3 nM). Furthermore, our in vivo experiments illustrated that curcumin significantly increases liver glycogen in fasting Balb/c mice. Our findings strongly suggest that the diverse pharmacological activities of curcumin are at least partially mediated by inhibition of GSK-3beta.

Topics: Algorithms; Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Binding Sites; Curcumin; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Mice; Mice, Inbred BALB C; Molecular Dynamics Simulation; NF-kappa B; Protein Kinase Inhibitors

Curcuminoids (a mixture of curcumin, bisdemethoxycurcumin and demethoxycurcumin) share vital pharmacological properties possessed by turmeric, a well known curry spice, considered useful in Alzheimer's disease (AD). The aim of this study was to evaluate if curcuminoids possess acetylcholinesterase (AChE) inhibitory and memory enhancing activities. The in-vitro and ex-vivo models of AChE inhibitory activity were used along with Morris water maze test to study the effect on memory in rats. Curcuminoids inhibited AChE in the in-vitro assay with IC(50) value of 19.67, bisdemethoxycurcumin 16.84, demethoxycurcumin 33.14 and curcumin 67.69 microM. In the ex-vivo AChE assay, curcuminoids and its individual components except curcumin showed dose-dependent (3-10 mg/kg) inhibition in frontal cortex and hippocampus. When studied for their effect on memory at a fixed dose (10 mg/kg), all compounds showed significant (p<0.001) and comparable effect in scopolamine-induced amnesia. These data indicate that curcuminoids and all individual components except curcumin possess pronounced AChE inhibitory activity. Curcumin was relatively weak in the in-vitro assay and without effect in the ex-vivo AChE model, while equally effective in memory enhancing effect, suggestive of additional mechanism(s) involved. Thus curcuminoids mixture might possess better therapeutic profile than curcumin for its medicinal use in AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Amnesia; Animals; Cholinesterase Inhibitors; Curcuma; Curcumin; Dose-Response Relationship, Drug; Hippocampus; Male; Maze Learning; Memory; Parasympatholytics; Phytotherapy; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Scopolamine

The study set out to determine (a) whether DNA damage is elevated in mice that carry mutations in the amyloid precursor protein (APP695swe) and presenilin 1 (PSEN1-dE9) that predispose to Alzheimer's disease (AD) relative to non-transgenic control mice, and (b) whether increasing the intake of dietary polyphenols from curcumin or grape seed extract could reduce genomic instability events in a transgenic mouse model for AD. DNA damage was measured using the micronucleus (MN) assay in both buccal mucosa and erythrocytes and an absolute telomere length assay for both buccal mucosa and olfactory bulb tissue. MN frequency tended to be higher in AD mice in both buccal mucosa (1.7-fold) and polychromatic erythrocytes (1.3-fold) relative to controls. Telomere length was significantly reduced by 91% (p=0.04) and non-significantly reduced by 50% in buccal mucosa and olfactory bulbs respectively in AD mice relative to controls. A significant 10-fold decrease in buccal MN frequency (p=0.01) was found for AD mice fed diets containing curcumin (CUR) or micro-encapsulated grape seed extract (MGSE) and a 7-fold decrease (p=0.02) for AD mice fed unencapsulated grape seed extract (GSE) compared to the AD group on control diet. Similarly, in polychromatic erythrocytes a significant reduction in MN frequency was found for the MGSE cohort (65.3%) (p<0.05), whereas the AD CUR and AD GSE groups were non-significantly reduced by 39.2 and 34.8% respectively compared to the AD Control. A non-significant 2-fold increase in buccal cell telomere length was evident for the CUR, GSE and MGSE groups compared to the AD control group. Olfactory bulb telomere length was found to be non-significantly 2-fold longer in mice fed on the CUR diet compared to controls. These results suggest potential protective effects of polyphenols against genomic instability events in different somatic tissues of a transgenic mouse model for AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Base Sequence; Cheek; Curcumin; Disease Models, Animal; DNA Primers; Female; Flavonoids; Genomic Instability; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Micronucleus Tests; Mutation; Olfactory Bulb; Phenols; Plant Extracts; Polyphenols; Presenilin-1; Seeds; Telomere; Vitis

Recent evidence indicates that curcumin (CUR), the principal curcuminoid of turmeric, exhibits antioxidant potential and protects the brain against various oxidative stressors. The aim of the present study was to examine the modulating impacts of CUR against cognitive deficits and oxidative damage in intracerebroventricular-streptozotocin (ICV-STZ) infused rats. Rats were injected bilaterally with ICV-STZ (3 mg/kg), while sham rats received the same volume of vehicle and then supplemented with CUR (80 mg/kg) for three weeks. After two weeks of ICV-STZ infusion, rats were tested for cognitive performance using passive avoidance and water maze tasks and then sacrificed for biochemical and histopathological assays. ICV-STZ rats showed significant cognitive deficits, which were significantly improved by CUR supplementation. CUR supplementation significantly augmented increased 4-hydroxynonenal (4-HNE) and malonaldehyde (MDA), thiobarbituric reactive substances (TBARS), hydrogen peroxide (H2O2), protein carbonyl (PC) and oxidized glutathione (GSSG); decreased levels of reduced glutathione (GSH) and its dependent enzymes (Glutathione peroxidase [GPx] and glutathione reductase [GR]) in the hippocampus and cerebral cortex; and increased choline acetyltransferase (ChAT) activity in the hippocampus of ICV-STZ rats. The study suggests that CUR is effective in preventing cognitive deficits, and might be beneficial for the treatment of sporadic dementia of Alzheimer's type (SDAT).

Topics: Alzheimer Disease; Animals; Brain; Cerebral Cortex; Choline O-Acetyltransferase; Cognition; Curcumin; Disease Models, Animal; Hippocampus; Injections, Intraventricular; Male; Nerve Degeneration; Neuroprotective Agents; Rats; Rats, Wistar; Reactive Oxygen Species; Streptozocin; Time Factors

Both insulin resistance (type II diabetes) and beta-amyloid (Abeta) oligomers are implicated in Alzheimer's disease (AD). Here, we investigate the role of Abeta oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. Increased phospho-IRS-1 is found in AD brain and insulin-resistant tissues from diabetics. Here, we report Abeta oligomers significantly increased active JNK and phosphorylation of IRS-1 (Ser616) and tau (Ser422) in cultured hippocampal neurons, whereas JNK inhibition blocked these responses. The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 months reduced phosphorylated JNK, IRS-1, and tau and prevented the degradation of total IRS-1. This was accompanied by improvement in Y-maze performance. Mice fed with fish oil and curcumin for 1 month had more significant effects on Y-maze, and the combination showed more significant inhibition of JNK, IRS-1, and tau phosphorylation. These data indicate JNK mediates Abeta oligomer inactivation of IRS-1 and phospho-tau pathology and that dietary treatment with fish oil/DHA, curcumin, or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Behavior, Animal; Cells, Cultured; Curcumin; Disease Models, Animal; Embryo, Mammalian; Enzyme Inhibitors; Fatty Acids, Omega-3; Hippocampus; Humans; Insulin Receptor Substrate Proteins; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Transgenic; Middle Aged; Neurons; Peptide Fragments; Phosphorylation; Postmortem Changes; Presenilin-1; Rats; Rats, Sprague-Dawley; Serine; Signal Transduction; tau Proteins

Abnormal aggregation of beta-amyloid (Abeta) peptides into toxic aggregates has been identified as a key event in Alzheimer's disease (AD). Inhibition of this process has thus emerged as a major therapeutic track against AD. The present work describes the synthesis and in vitro study of a novel class of inhibitors. Two copies of Abeta-binding motifs (either curcumin or the KLVFFA peptide) are clicked via copper(I)-mediated azide-alkyne cycloaddition on a constrained cyclopeptide scaffold designed to interfere with Abeta aggregation. Our conjugates strongly inhibit amyloid fibril formation from Abeta(40) at low inhibitor to Abeta molar ratios (e.g., 0.02:1 in the case of the KLVFFA conjugate) at which Abeta-binding motifs alone are fully inactive (thioflavin T assays and atomic force microscopy observation). This work highlights the value of combining Abeta-recognition domains with a steric hindrance-inducing scaffold for preventing amyloid fibril formation.

Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid beta-Peptides; Curcumin; Drug Design; Humans; Peptide Fragments

Inhibition of amyloid-beta (Abeta) aggregation is an attractive therapeutic strategy for Alzheimer's disease (AD). Certain phenolic compounds have been reported to have anti-Abeta aggregation effects in vitro. This study systematically investigated the effects of phenolic compounds on AD model transgenic mice (Tg2576). Mice were fed five phenolic compounds (curcumin, ferulic acid, myricetin, nordihydroguaiaretic acid (NDGA), and rosmarinic acid (RA)) for 10 months from the age of 5 months. Immunohistochemically, in both the NDGA- and RA-treated groups, Abeta deposition was significantly decreased in the brain (P < 0.05). In the RA-treated group, the level of Tris-buffered saline (TBS)-soluble Abeta monomers was increased (P < 0.01), whereas that of oligomers, as probed with the A11 antibody (A11-positive oligomers), was decreased (P < 0.001). However, in the NDGA-treated group, the abundance of A11-positive oligomers was increased (P < 0.05) without any change in the levels of TBS-soluble or TBS-insoluble Abeta. In the curcumin- and myricetin-treated groups, changes in the Abeta profile were similar to those in the RA-treated group, but Abeta plaque deposition was not significantly decreased. In the ferulic acid-treated group, there was no significant difference in the Abeta profile. These results showed that oral administration of phenolic compounds prevented the development of AD pathology by affecting different Abeta aggregation pathways in vivo. Clinical trials with these compounds are necessary to confirm the anti-AD effects and safety in humans.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cinnamates; Coumaric Acids; Curcumin; Depsides; Disease Models, Animal; Female; Flavonoids; Humans; Immunohistochemistry; Masoprocol; Mice; Mice, Transgenic; Phenols; Rosmarinic Acid; Signal Transduction

Increasing evidence suggests that many neurons may die through apoptosis in Alzheimer's disease (AD). Mitochondrial dysfunction has been implicated in this process of neuronal cell death. One promising approach for preventing AD is based upon anti-apoptosis to decrease death of nerve cells. In this study, we observed the memory improving properties of curcumin in mice and investigated the neuroprotective effect of curcumin in vitro and in vivo.. The mice were given AlCl(3) orally and injections of D-galactose intraperitoneally for 90 days to establish the AD animal model. From day 45, the curcumin group was treated with curcumin for 45 days. Subsequently, the step-through test, neuropathological changes in the hippocampus and the expression of Bax and Bcl-2 were carried out to evaluate the effect of curcumin on the AD model mice. In cultured PC12 cells, AlCl(3) exposure induced apoptosis. The MTT assay was used to measure cell viabilities; flow cytometric analysis to survey the rate of cell apoptosis; DNA-binding fluorochrome Hoechst 33258 to observe nuclei changes in apoptotic cells and Western blot analysis of Bax, Bcl-2 to investigate the mechanisms by which curcumin protects cells from toxicity.. Curcumin significantly improved the memory ability of AD mice in the step-through test, as indicated by the reduced number of step-through errors (P < 0.05) and prolonged step-through latency (P < 0.05). Curcumin also attenuated the neuropathological changes in the hippocampus and inhibited apoptosis accompanied by an increase in Bcl-2 level (P < 0.05), but the activity of Bax did not change (P > 0.05). AlCl(3) significantly reduced the viability of PC12 cells (P < 0.01). Curcumin increased cell viability in the presence of AlCl(3) (P < 0.01). The rate of apoptosis decreased significantly in the curcumin group (P < 0.05) when measured by flow cytometric analysis. Curcumin protected cells by increasing Bcl-2 level (P < 0.05), but the level of Bax did not change (P > 0.05).. This study demonstrates that curcumin improves the memory ability of AD mice and inhibits apoptosis in cultured PC12 cells induced by AlCl(3). Its mechanism may involve enhancing the level of Bcl-2.

Topics: Aluminum Chloride; Aluminum Compounds; Alzheimer Disease; Animals; Apoptosis; Cells, Cultured; Chlorides; Curcumin; Disease Models, Animal; Female; Learning; Memory; Mice; Neuroprotective Agents; PC12 Cells; Rats

The synthesis of a novel series of aminostyrylbenzofuran derivatives 1a-w and their inhibitory activities for Abeta fibril formation were described. All the synthesized compounds were evaluated by thioflavin T (ThT) assay and displayed potent inhibitory activities for Abeta fibril formation. Among them, compounds 1i and 1q exhibited excellent inhibitory activities (IC(50)=0.07 and 0.08 microM, respectively) than those of Curcumin (IC(50)=0.80 microM) and IMSB (IC(50)=8.00 microM) as reference compounds. Both compounds were selected as promising candidates for further biological evaluation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzofurans; Benzothiazoles; Benzoxazoles; Chemistry, Pharmaceutical; Curcumin; Drug Design; Electrons; Humans; Inhibitory Concentration 50; Models, Chemical; Peptide Fragments; Structure-Activity Relationship; Styrenes; Thiazoles

Curcumin binds to the amyloid beta peptide (Abeta) and inhibits or modulates amyloid precursor protein (APP) metabolism. Therefore, curcumin-derived isoxazoles and pyrazoles were synthesized to minimize the metal chelation properties of curcumin. The decreased rotational freedom and absence of stereoisomers was predicted to enhance affinity toward Abeta(42) aggregates. Accordingly, replacement of the 1,3-dicarbonyl moiety with isosteric heterocycles turned curcumin analogue isoxazoles and pyrazoles into potent ligands of fibrillar Abeta(42) aggregates. Additionally, several compounds are potent inhibitors of tau protein aggregation and depolymerized tau protein aggregates at low micromolar concentrations.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Cell Proliferation; Cells, Cultured; Chickens; Curcumin; Enzyme Inhibitors; Fluorescence Resonance Energy Transfer; Humans; Inhibitory Concentration 50; Isoxazoles; Magnetic Resonance Spectroscopy; Pyrazoles; Radioligand Assay; tau Proteins

Curcumin can reduce inflammation and neurodegeneration, but its chemical instability and metabolism raise concerns, including whether the more stable metabolite tetrahydrocurcumin (TC) may mediate efficacy. We examined the antioxidant, anti-inflammatory, or anti-amyloidogenic effects of dietary curcumin and TC, either administered chronically to aged Tg2576 APPsw mice or acutely to lipopolysaccharide (LPS)-injected wild-type mice. Despite dramatically higher drug plasma levels after TC compared with curcumin gavage, resulting brain levels of parent compounds were similar, correlating with reduction in LPS-stimulated inducible nitric-oxide synthase, nitrotyrosine, F2 isoprostanes, and carbonyls. In both the acute (LPS) and chronic inflammation (Tg2576), TC and curcumin similarly reduced interleukin-1beta. Despite these similarities, only curcumin was effective in reducing amyloid plaque burden, insoluble beta-amyloid peptide (Abeta), and carbonyls. TC had no impact on plaques or insoluble Abeta, but both reduced Tris-buffered saline-soluble Abeta and phospho-c-Jun NH(2)-terminal kinase (JNK). Curcumin but not TC prevented Abeta aggregation. The TC metabolite was detected in brain and plasma from mice chronically fed the parent compound. These data indicate that the dienone bridge present in curcumin, but not in TC, is necessary to reduce plaque deposition and protein oxidation in an Alzheimer's model. Nevertheless, TC did reduce neuroinflammation and soluble Abeta, effects that may be attributable to limiting JNK-mediated transcription. Because of its favorable safety profile and the involvement of misfolded proteins, oxidative damage, and inflammation in multiple chronic degenerative diseases, these data relating curcumin dosing to the blood and tissue levels required for efficacy should help translation efforts from multiple successful preclinical models.

Topics: Alzheimer Disease; Animals; Biological Availability; Curcumin; Disease Models, Animal; Female; Inflammation; Male; Mice; Mice, Inbred C57BL; Structure-Activity Relationship

Polymerization of the amyloid beta-peptide (Abeta) has been identified as one of the major characteristics of Alzheimer's disease (AD). Thus, finding molecules to prevent the aggregation of Abeta could be of therapeutic value in AD. We describe an original routine in vitro assay to search for inhibitors of Abeta(25-35) fibril formation which uses UV-visible measurements and electron microscopy (EM). In particular, this routine assay was used to examine the effects of stilbenes, a well-known polyphenol class, as inhibitors of Abeta fibril formation. The inhibitory properties of resveratrol (RES), piceid (PIC), resveratrol diglucoside (DIG), piceatannol (PIA), astringine (AST), and viniferin (VIN) were characterized and compared. RES and PIC effectively and dose-dependently inhibited Abeta polymerization while other polyphenols exerted less inhibition. Although the mechanism of anti-amyloidogenic activity is still unknown, these results support the hypothesis that stilbenes could be of therapeutic value in AD.

Topics: Algorithms; Alzheimer Disease; Amyloid beta-Peptides; Animals; Bradykinin; Curcumin; Microscopy, Electron; PC12 Cells; Peptide Fragments; Polymers; Rats; Solutions; Spectrophotometry, Ultraviolet; Stilbenes

Topics: Alzheimer Disease; Curcuma; Curcumin; History, 20th Century; History, Ancient; Humans; Medicine, Traditional; Neoplasms; Patents as Topic; Phytotherapy; Rhizome; Spices

The antioxidant potency of three natural polyphenols, resveratrol, curcumin, and genistein, was compared by using the two human models: oxymodified with H(2)O(2) and homocysteine (Hcy) G proteins in the postmortem frontal cortex (FC) membranes of age-matched control and Alzheimer's disease (AD) subjects; and Cu(2+)-induced oxidation of plasma low-density lipoproteins (LDL). In Co, 3-10 microM polyphenols dose-dependently depressed the G protein 25% stimulation induced by 10 microM H(2)O(2) or 500 microM Hcy. Resveratrol revealed significantly higher antioxidativity than curcumin or genistein. In AD, the antioxidativity of polyphenols showed no significant differences. Polyphenols (1 microM) significantly increased the LDL oxidation lag time (oxyresistance) as compared with control, the effect of resveratrol being most potent. Due to the dual antioxidant mechanism, the investigated polyphenols, particularly resveratrol, should have preferences for the preventive-therapeutic use in age-related oxidative stress-based pathologies.

Topics: Aged, 80 and over; Aging; Alzheimer Disease; Antioxidants; Curcumin; Female; Flavonoids; Genistein; GTP-Binding Proteins; Humans; Oxidative Stress; Phenols; Plant Preparations; Polyphenols; Resveratrol; Signal Transduction; Stilbenes

Topics: Alzheimer Disease; Back Pain; Coffee; Curcumin; Drinking Behavior; Fruit; Humans; Remission, Spontaneous; Spices

Alzheimer's disease (AD) is characterized by senile plaques and neurodegeneration although the neurotoxic mechanisms have not been completely elucidated. It is clear that both oxidative stress and inflammation play an important role in the illness. The compound curcumin, with a broad spectrum of anti-oxidant, anti-inflammatory, and anti-fibrilogenic activities may represent a promising approach for preventing or treating AD. Curcumin is a small fluorescent compound that binds to amyloid deposits. In the present work we used in vivo multiphoton microscopy (MPM) to demonstrate that curcumin crosses the blood-brain barrier and labels senile plaques and cerebrovascular amyloid angiopathy (CAA) in APPswe/PS1dE9 mice. Moreover, systemic treatment of mice with curcumin for 7 days clears and reduces existing plaques, as monitored with longitudinal imaging, suggesting a potent disaggregation effect. Curcumin also led to a limited, but significant reversal of structural changes in dystrophic dendrites, including abnormal curvature and dystrophy size. Together, these data suggest that curcumin reverses existing amyloid pathology and associated neurotoxicity in a mouse model of AD. This approach could lead to more effective clinical therapies for the prevention of oxidative stress, inflammation and neurotoxicity associated with AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Curcumin; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurites; Neurons; Neuroprotective Agents; Presenilin-1

We have tested a hypothesis that the natural product curcuminoids, which has epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid-beta (Abeta) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport Abeta into endosomes and lysosomes, and AD monocytes do not efficiently clear Abeta from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport Abeta to endosomes and lysosomes, and monocytes of these subjects clear Abeta in AD brain sections. Upon Abeta stimulation, mononuclear cells of normal subjects up-regulate the transcription of beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3) (P < 0.001) and other genes, including Toll like receptors (TLRs), whereas mononuclear cells of AD patients generally down-regulate these genes. Defective phagocytosis of Abeta may be related to down-regulation of MGAT3, as suggested by inhibition of phagocytosis by using MGAT3 siRNA and correlation analysis. Transcription of TLR3, bditTLR4, TLR5, bditTLR7, TLR8, TLR9, and TLR10 upon Abeta stimulation is severely depressed in mononuclear cells of AD patients in comparison to those of control subjects. In mononuclear cells of some AD patients, the curcuminoid compound bisdemethoxycurcumin may enhance defective phagocytosis of Abeta, the transcription of MGAT3 and TLRs, and the translation of TLR2-4. Thus, bisdemethoxycurcumin may correct immune defects of AD patients and provide a previously uncharacterized approach to AD immunotherapy.

Topics: Acyltransferases; Aged; Alzheimer Disease; Amyloid beta-Peptides; Cell Communication; Curcumin; Diarylheptanoids; Down-Regulation; Humans; Immunity, Innate; Immunotherapy; Lymphocytes; Macrophages; Phagocytosis; Protein Biosynthesis; Protein Transport; RNA, Small Interfering; Toll-Like Receptors; Transcription, Genetic

It is demonstrated by using high-level ab initio computations that the yellow curcumin pigment, bis-(4-hydroxy-3-methoxyphenyl)-1,6-diene-3,5-dione, in the east Indian root plant turmeric (Curcuma longa) exhibits unique charge and bonding characteristics that facilitate penetration into the blood-brain barrier and binding to amyloid beta (Abeta). Alzheimer's disease is caused by Abeta accumulation in the brain cells combined with oxidative stress and inflammation. Consistent with the recent experimental work by Cole and co-workers (Yang, F., et al. J. Biol. Chem. 2004, 280, 5892-5901) that demonstrates curcumin pigment's binding ability to Abeta both in vivo and in vitro, it is shown here that curcumin possesses suitable charge and bonding features to facilitate the binding to Abeta. In addition, curcumin's anti-inflammatory and antioxidant properties are also attributed to electronic and structural features. It is shown that the presence of an enolic center and two phenolic polar groups separated by an essentially hydrophobic bridge of a conjugated network provides both hydrophobic and hydrophilic features to the curcumin pigment, thereby facilitating penetration into the blood-brain barrier through the former property and then binding to Abeta oligomer through the latter property. Both density functional and Møller-Plesset perturbation (MP2) computations have been carried out on the curcumin pigment to obtain fully optimized geometries in the gas phase and aqueous solution and also the atomic charges. Different isomers (keto and enol forms) have been considered to show that the enol form is the most favored and has all of the properties for an ideal antioxidant with also features to penetrate the blood-brain barrier and to bind to Abeta. This is demonstrated with natural bond charges, highest occupied and lowest unoccupied molecular orbitals, dipole moments, and Laplacian plots. The computed ionization potential and electron affinity show that curcumin has a low molecular hardness and thus has a propensity to dissociate its phenolic -OH, and the resulting charge undergoes delocalization throughout the structure, resulting in excitonic features. This feature seems to be also important for its binding capability to human proteins such as human serum albumin and Abeta.

Topics: Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Binding Sites; Blood-Brain Barrier; Computational Biology; Curcuma; Curcumin; Humans; Molecular Structure; Phytotherapy; Plant Extracts; Spices

Topics: Alzheimer Disease; Antioxidants; Capsaicin; Cinnamomum zeylanicum; Curcumin; Cystic Fibrosis; Health Promotion; Humans; Hypercholesterolemia; Neoplasms; Phytotherapy; Plant Structures; Plants, Medicinal; Salvia officinalis; Spices

Treatment of Alzheimer's disease (AD) is difficult due to ignorance of its pathogenesis. AD patients have defects in phagocytosis of amyloid-beta (1-42) (Abeta) in vitro by the innate immune cells, monocyte/macrophages and in clearance of Abeta plaques [5]. The natural product curcuminoids enhanced brain clearance of Abeta in animal models. We, therefore, treated macrophages of six AD patients and 3 controls by curcuminoids in vitro and measured Abeta uptake using fluorescence and confocal microscopy. At baseline, the intensity of Abeta uptake by AD macrophages was significantly lower in comparison to control macrophages and involved surface binding but no intracellular uptake. After treatment of macrophages with curcuminoids, Abeta uptake by macrophages of three of the six AD patients was significantly (P<0.001 to 0.081) increased. Confocal microscopy of AD macrophages responsive to curcuminoids showed surface binding in untreated macrophages but co-localization with phalloidin in an intracellular compartment after treatment. Immunomodulation of the innate immune system by curcuminoids might be a safe approach to immune clearance of amyloidosis in AD brain.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cognition Disorders; Curcumin; Female; Humans; Immunologic Factors; Macrophages; Male; Microscopy, Confocal; Microscopy, Fluorescence; Middle Aged; Neuropsychological Tests; Phagocytosis

Alzheimer's disease (AD) involves amyloid beta (Abeta) accumulation, oxidative damage, and inflammation, and risk is reduced with increased antioxidant and anti-inflammatory consumption. The phenolic yellow curry pigment curcumin has potent anti-inflammatory and antioxidant activities and can suppress oxidative damage, inflammation, cognitive deficits, and amyloid accumulation. Since the molecular structure of curcumin suggested potential Abeta binding, we investigated whether its efficacy in AD models could be explained by effects on Abeta aggregation. Under aggregating conditions in vitro, curcumin inhibited aggregation (IC(50) = 0.8 microM) as well as disaggregated fibrillar Abeta40 (IC(50) = 1 microM), indicating favorable stoichiometry for inhibition. Curcumin was a better Abeta40 aggregation inhibitor than ibuprofen and naproxen, and prevented Abeta42 oligomer formation and toxicity between 0.1 and 1.0 microM. Under EM, curcumin decreased dose dependently Abeta fibril formation beginning with 0.125 microM. The effects of curcumin did not depend on Abeta sequence but on fibril-related conformation. AD and Tg2576 mice brain sections incubated with curcumin revealed preferential labeling of amyloid plaques. In vivo studies showed that curcumin injected peripherally into aged Tg mice crossed the blood-brain barrier and bound plaques. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small beta-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Abeta as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Benzothiazoles; Biphenyl Compounds; Blood-Brain Barrier; Brain; Cell Line, Tumor; Congo Red; Curcumin; Diamines; Humans; Ibuprofen; Mice; Mice, Transgenic; Naproxen; Peptide Fragments; Plaque, Amyloid; Protein Binding; Protein Denaturation; Protein Structure, Quaternary; Pyridazines; Solubility; Thiazoles

Topics: Alzheimer Disease; Amyloid; Blood-Brain Barrier; Curcuma; Curcumin; Humans

The use of turmeric, derived from the root of the plant Curcuma longa, for treatment of different inflammatory diseases has been described in Ayurveda and in traditional Chinese medicine for thousands of years. The active component of turmeric responsible for this activity, curcumin, was identified almost two centuries ago. Modern science has revealed that curcumin mediates its effects by modulation of several important molecular targets, including transcription factors (e.g., NF-kappaB, AP-1, Egr-1, beta-catenin, and PPAR-gamma), enzymes (e.g., COX2, 5-LOX, iNOS, and hemeoxygenase-1), cell cycle proteins (e.g., cyclin D1 and p21), cytokines (e.g., TNF, IL-1, IL-6, and chemokines), receptors (e.g., EGFR and HER2), and cell surface adhesion molecules. Because it can modulate the expression of these targets, curcumin is now being used to treat cancer, arthritis, diabetes, Crohn's disease, cardiovascular diseases, osteoporosis, Alzheimer's disease, psoriasis, and other pathologies. Interestingly, 6-gingerol, a natural analog of curcumin derived from the root of ginger (Zingiber officinalis), exhibits a biologic activity profile similar to that of curcumin. The efficacy, pharmacologic safety, and cost effectiveness of curcuminoids prompt us to "get back to our roots."

Topics: Alzheimer Disease; Arthritis, Rheumatoid; Atherosclerosis; Blood Glucose; Curcumin; Diabetes Mellitus, Type 2; Humans; India; Inflammation; Multiple Sclerosis; Myocardial Infarction; Plant Roots; Transcription, Genetic

Inhibition of the accumulation of amyloid beta-peptide (Abeta) and the formation of beta-amyloid fibrils (fAbeta) from Abeta, as well as the destabilization of preformed fAbeta in the central nervous system, would be attractive therapeutic targets for the treatment of Alzheimer's disease (AD). We reported previously that nordihydroguaiaretic acid (NDGA) and wine-related polyphenols inhibit fAbeta formation from Abeta(1-40) and Abeta(1-42) and destabilize preformed fAbeta(1-40) and fAbeta(1-42) dose-dependently in vitro. Using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, we examined the effects of curcumin (Cur) and rosmarinic acid (RA) on the formation, extension, and destabilization of fAbeta(1-40) and fAbeta(1-42) at pH 7.5 at 37 degrees C in vitro. We next compared the anti-amyloidogenic activities of Cur and RA with NDGA. Cur and RA dose-dependently inhibited fAbeta formation from Abeta(1-40) and Abeta(1-42), as well as their extension. In addition, they dose-dependently destabilized preformed fAbetas. The overall activities of Cur, RA, and NDGA were similar. The effective concentrations (EC(50)) of Cur, RA, and NDGA for the formation, extension, and destabilization of fAbetas were in the order of 0.1-1 microM. Although the mechanism by which Cur and RA inhibit fAbeta formation from Abeta and destabilize preformed fAbeta in vitro remains unclear, they could be a key molecule for the development of therapeutics for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Anti-Inflammatory Agents, Non-Steroidal; Benzothiazoles; Cinnamates; Curcumin; Depsides; Dose-Response Relationship, Drug; In Vitro Techniques; Kinetics; Lipoxygenase Inhibitors; Masoprocol; Microscopy, Electron; Microscopy, Polarization; Neurofibrillary Tangles; Peptide Fragments; Platelet Aggregation Inhibitors; Rosmarinic Acid; Spectrometry, Fluorescence; Thiazoles; Time Factors

Curcumin is a polyphenolic diketone from turmeric. Because of its anti-oxidant and anti-inflammatory effects, it was tested in animal models of Alzheimer's disease, reducing levels of amyloid and oxidized proteins and preventing cognitive deficits. An alternative mechanism of these effects is metal chelation, which may reduce amyloid aggregation or oxidative neurotoxicity. Metals can induce Abeta aggregation and toxicity, and are concentrated in AD brain. Chelators desferrioxamine and clioquinol have exhibited anti-AD effects. Using spectrophotometry, we quantified curcumin affinity for copper, zinc, and iron ions. Zn2+ showed little binding, but each Cu2+ or Fe2+ ion appeared to bind at least two curcumin molecules. The interaction of curcumin with copper reached half-maximum at approximately 3-12 microM copper and exhibited positive cooperativity, with Kd1 approximately 10-60 microM and Kd2 approximately 1.3 microM (for binding of the first and second curcumin molecules, respectively). Curcumin-iron interaction reached half-maximum at approximately 2.5-5 microM iron and exhibited negative cooperativity, with Kd1 approximately 0.5-1.6 microM and Kd2 approximately 50-100 microM. Curcumin and its metabolites can attain these levels in vivo, suggesting physiological relevance. Since curcumin more readily binds the redox-active metals iron and copper than redox-inactive zinc, curcumin might exert a net protective effect against Abeta toxicity or might suppress inflammatory damage by preventing metal induction of NF-kappaB.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Anti-Inflammatory Agents, Non-Steroidal; Binding Sites; Chelating Agents; Cognition Disorders; Copper; Curcumin; Humans; Iron

From Curcuma longa, two novel compounds, 4' '-(3' "-methoxy-4' "-hydroxyphenyl)-2' '-oxo-3' '-enebutanyl 3-(3'-methoxy-4'hydroxyphenyl)propenoate (calebin-A, 1) and 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one (2), and seven known compounds, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (curcumin, 3), 1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (demethoxycurcumin, 4), 1,7-bis(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (bisdemethoxycurcumin, 5), 1-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-6-heptene-3,5-dione (6), 1,7-bis(4-hydroxyphenyl)-1-heptene-3,5-dione (7), 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (8), and 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one (9), were isolated following a bioassay-guided fractionation scheme utilizing an assay to detect protection of PC12 cells from beta-amyloid insult. Compounds 1, 3-5, and 7 were found to more effectively protect PC12 cells from betaA insult (ED(50) = 0.5-10 microg/mL) than Congo red (10) (ED(50) = 37-39 microg/mL).

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Biological Products; Cell Survival; Cinnamates; Curcuma; Curcumin; Diarylheptanoids; Diterpenes; Molecular Structure; Monoterpenes; PC12 Cells; Peptide Fragments; Plants, Medicinal; Rats

beta-Amyloid (betaA) induced oxidative stress is a well-established pathway of neuronal cell death in Alzheimer's disease. From turmeric, Curcuma longa L. (Zingiberaceae), three curcuminoids, curcumin, demethoxycurcumin, and bisdemethoxycurcumin, were found to protect PC12 rat pheochromocytoma and normal human umbilical vein endothelial (HUVEC) cells from betaA(1-42) insult, as measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction assay. ED(50) values of curcumin, demethoxycurcumin, and bisdemethoxycurcumin toward PC12 and HUVEC cells were 7.1+/-0.3, 4.7+/-0.1, 3.5+/-0.2 microg/ml and 6.8+/-0.4, 4.2+/-0.3, and 3.0+/-0.3 microg/ml, respectively. These compounds were better antioxidants than alpha-tocopherol as determined by DPPH radical trapping experiment. alpha-Tocopherol did not protect the cells from betaA(1-42) insult even at>50 microg/ml concentration. The results suggest that these compounds may be protecting the cells from betaA(1-42) insult through antioxidant pathway.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cell Survival; Coumaric Acids; Curcumin; Diarylheptanoids; Endothelium, Vascular; Humans; PC12 Cells; Peptide Fragments; Rats; Umbilical Veins; Zingiberales

Inflammation in Alzheimer's disease (AD) patients is characterized by increased cytokines and activated microglia. Epidemiological studies suggest reduced AD risk associates with long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas chronic ibuprofen suppressed inflammation and plaque-related pathology in an Alzheimer transgenic APPSw mouse model (Tg2576), excessive use of NSAIDs targeting cyclooxygenase I can cause gastrointestinal, liver, and renal toxicity. One alternative NSAID is curcumin, derived from the curry spice turmeric. Curcumin has an extensive history as a food additive and herbal medicine in India and is also a potent polyphenolic antioxidant. To evaluate whether it could affect Alzheimer-like pathology in the APPSw mice, we tested a low (160 ppm) and a high dose of dietary curcumin (5000 ppm) on inflammation, oxidative damage, and plaque pathology. Low and high doses of curcumin significantly lowered oxidized proteins and interleukin-1beta, a proinflammatory cytokine elevated in the brains of these mice. With low-dose but not high-dose curcumin treatment, the astrocytic marker GFAP was reduced, and insoluble beta-amyloid (Abeta), soluble Abeta, and plaque burden were significantly decreased by 43-50%. However, levels of amyloid precursor (APP) in the membrane fraction were not reduced. Microgliosis was also suppressed in neuronal layers but not adjacent to plaques. In view of its efficacy and apparent low toxicity, this Indian spice component shows promise for the prevention of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Antioxidants; Brain; Curcumin; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Enzyme Inhibitors; Female; Glial Fibrillary Acidic Protein; Interleukin-1; Male; Mice; Mice, Transgenic; Microglia; Oxidation-Reduction; Oxidative Stress; Solubility; Spices