stilbenes and Alzheimer-Disease

Dementia is a collection of symptoms affecting a person's cognition. Dementia is debilitating, and therefore, finding an effective treatment is of utmost importance. Resveratrol, which exhibits neuroprotective effects, has low bioavailability. However, its glucoside polydatin is more bioavailable. Here, the evidence that supports the protective role of polydatin against dementia- related diseases such as Alzheimer's disease, vascular dementia, alcohol-related dementia, and Lewy body dementias is presented. The beneficial effects of polydatin from a mechanistic perspective are specifically emphasized in this review. Future directions in this area of research are also discussed.

Topics: Alzheimer Disease; Dementia; Glucosides; Humans; Lewy Body Disease; Stilbenes

Pterostilbene, 3',5'-dimethoxy-4-hydroxystilbene, is a resveratrol analogue and has been reported to have similar and often potent health-promoting properties. Pterostilbene has been shown to reduce weight gain, liver fat, plasma cholesterol, adiposity, inflammatory biomarkers, blood glucose, and other physiological characteristics of metabolic diseases in animal models. Studies on pterostilbene suggest that it may improve risk factors associated with diabetes, cardiovascular disease, fatty liver diseases, Alzheimer's disease, and other neurodegenerative diseases. Many of the extensive studies on the potential health benefits of pterostilbene were conducted by Dr. Agnes Rimando, a scientist with the United States Department of Agriculture, in collaboration with many U.S. and other international research groups. This review highlights the pterostilbene research of Dr. Rimando.

Topics: Alzheimer Disease; Animals; Antioxidants; Cardiovascular Diseases; Humans; Obesity; Stilbenes

Resveratrol is a natural phytoestrogen with neuroprotective properties. Polyphenolic compounds including resveratrol exert in vitro antioxidant, anti-inflammatory, and antiamyloid effects. Resveratrol and its derivative pterostilbene are able to cross the blood-brain barrier and to influence brain activity. The present short review summarizes the available evidence regarding the effects of these polyphenols on pathology and cognition in animal models and human subjects with dementia. Numerous investigations in cellular and mammalian models have associated resveratrol and pterostilbene with protection against dementia syndromes such as Alzheimer's disease (AD) and vascular dementia. The neuroprotective activity of resveratrol and pterostilbene demonstrated in in vitro and in vivo studies suggests a promising role for these compounds in the prevention and treatment of dementia. In comparison to resveratrol, pterostilbene appears to be more effective in combatting brain changes associated with aging. This may be attributed to the more lipophilic nature of pterostilbene with its two methoxyl groups compared with the two hydroxyl groups of resveratrol. The findings of available intervention trials of resveratrol in individuals with mild cognitive impairment or AD do not provide evidence of neuroprotective or therapeutic effects. Future clinical trials should be conducted with long-term exposure to preparations of resveratrol and pterostilbene with high bioavailability. © 2017 BioFactors, 44(1):83-90, 2018.

Topics: Alzheimer Disease; Animals; Antioxidants; Biological Transport; Blood-Brain Barrier; Brain; Clinical Trials as Topic; Cognitive Dysfunction; Dementia; Disease Models, Animal; Humans; Maze Learning; Neuroprotective Agents; Resveratrol; Stilbenes

A number of independent studies have shown the contribution of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the pathogenesis of several neurodegenerative disorders. Indeed, GAPDH aggregates have been found in many post-mortem samples of brains of patients diagnosed with Alzheimer's and Parkinson disease. Currently, it is accepted that GAPDH-mediated cell death pathways in the neurodegenerative processes are associated with apoptosis caused by GAPDH nuclear translocation and excessive aggregation under oxidative stress conditions. Also the role of GAPDH in neurodegenerative diseases is linked to it directly binding to specific amyloidogenic proteins and petides such as β-amyloid precursor protein, β-amyloid peptide and tau protein in Alzheimer's disease, huntingtin in Huntington's disease and α-synuclein in Parkinson disease. One of the latest studies indicated that GAPDH aggregates significantly accelerate amyloidogenesis of the β-amyloid peptide, which implies that aggregates of GAPDH may act as a specific aggregation "seed" in vitro. Previous detailed studies revealed that the active-site cysteine (Cys152) of GAPDH plays an essential role in the oxidative stress-induced aggregation of GAPDH associated with cell death. Furthermore, oxidative modification of this cysteine residue initiates the translocation of the enzyme to the nucleus, subsequently leading to apoptosis. The crystallographic structure of GAPDH shows that the Cys152 residue is located close to the surface of the molecule in a hydrophilic environment, which means that it can react with low molecular weight compounds such as hydroxynonenal or piceatannol. Therefore, it is highly possible that GAPDH may serve as a target for small molecule compounds with the potential to slow down or prevent the progression of neurodegenerative disorders. Recently appearing new evidence has highlighted the significance of low molecular weight compounds in counteracting the oxidation of GAPDH and consequently its aggregation and other unfavourable pathological processes. Hence, this review aims to present all recent findings concerning molecules that are able to interact with GAPDH and counteract its aggregation and translocation to the nucleus.

Topics: Active Transport, Cell Nucleus; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apoptosis; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Neurodegenerative Diseases; Oxidative Stress; Protein Aggregation, Pathological; Protein Structure, Secondary; Protein Structure, Tertiary; Stilbenes; tau Proteins

Topics: Alzheimer Disease; Blood-Brain Barrier; Double-Blind Method; Humans; Resveratrol; Sirtuins; Stilbenes; Treatment Outcome

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders over the age of 65 years old. Although several underlying mechanisms for explaining the pathogenesis of AD are elucidated, the effective supplements or drugs for the intervention of AD are still limited. Recently, impaired autophagy associated with miRNA dysfunction has been reported to involve in aging and aging-related neurodegenerative diseases. Thus, the activation of autophagy through effectively regulating miRNAs may become a potential target for the prevention or treatment of AD. Mounting evidence from in vitro and in vivo AD models has demonstrated that resveratrol, one of polyphenolic compounds, can exert neuroprotective role in neurodegenerative diseases especially AD. In this review, the regulation of miRNAs and autophagy using resveratrol during the prevention and treatment of AD are systematically discussed, which will be beneficial to establish a target for the direct link between pharmacological intervention and AD in the future.

Topics: Alzheimer Disease; Animals; Autophagy; Brain; Cognition; Humans; Inflammation Mediators; MicroRNAs; Neuroprotective Agents; Resveratrol; Signal Transduction; Stilbenes

The amyloid-beta (Aβ) hypothesis that dyshomeostasis between Aβ production and clearance is a very early, key molecular factor in the etiology of Alzheimer's disease (AD) has been proposed and examined in the AD research field. Scientists have focused on seeking natural products or drugs to influence the dynamic equilibrium of Aβ, targeting production and clearance of Aβ. There is emerging evidence that resveratrol (Res), a naturally occurring polyphenol mainly found in grapes and red wine, acts on AD in numerous in vivo and in vitro models. Res decreases the amyloidogenic cleavage of the amyloid precursor protein (APP), enhances clearance of amyloid beta-peptides, and reduces Aβ aggregation. Moreover, Res also protects neuronal functions through its antioxidant properties. This review discusses the action of Res on Aβ production, clearance and aggregation and multiple potential mechanisms, providing evidence of the useful of Res for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Humans; Neurons; Resveratrol; Stilbenes

Alzheimer's disease (AD) is the leading cause of dementia in the elderly and is characterized by progressive cognitive and memory deficits. The pathological hallmarks of AD include extracellular senile plaques and intracellular neurofibrillary tangles. Although several mechanisms have been used to explain the underlying pathogenesis of AD, current treatment regimens remain inadequate. The neuroprotective effects of the polyphenolic stilbene resveratrol (3,5,4'-trihydroxy-trans-stilbene) have been investigated in several in vitro and in vivo models of AD. The current review discusses the multiple potential mechanisms of action of resveratrol on the pathobiology of AD. Moreover, due to the limited pharmacokinetic parameters of resveratrol, multiple strategies aimed at increasing the bioavailability of resveratrol have also been addressed.

Topics: Alzheimer Disease; Animals; Autophagy; Humans; Mitochondria; Nerve Degeneration; Oxidative Stress; Resveratrol; Stilbenes

In the last decade, several radiolabeled compounds have been developed for the imaging in vivo of amyloid pathology by means of Positron Emission Tomography (PET). Among these, 18F Florbetaben appear to be one of the most reliable for its high affinity for amyloid plaques in brain and its radio-chemical properties that make it usable in common clinical routine. The aim of this review is to provide a general overview of the application in vivo of 18F Florbetaben, describing for first the physiopathological basis of amyloid pathology. Afterwards, the chemical characteristics of this radiolabeled compound will be described, with a particular attention to the synthesis process and the kinetic in vivo. An overview on the imaging protocols and image interpretation will be provided as well and, as a last aspect, the results of the main studies performed in subjects with advanced and early AD will be summarized.

Topics: Alzheimer Disease; Aniline Compounds; Animals; Brain; Humans; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes

Amyloid imaging represents a significant advance as an adjunct in the diagnosis of Alzheimer's disease (AD) because it is the first imaging modality that identifies in vivo changes known to be associated with the pathogenesis. Initially,

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Biomarkers; Brain; Clinical Trials as Topic; Ethylene Glycols; Humans; Nitriles; Positron-Emission Tomography; Radiopharmaceuticals; Sensitivity and Specificity; Stilbenes; Thiazoles; Translational Research, Biomedical

Our current therapeutic drugs for Alzheimer's disease are predominantly derived from the alkaloid class of plant phytochemicals. These drugs, such as galantamine and rivastigmine, attenuate the decline in the cholinergic system but, as the alkaloids occupy the most dangerous end of the phytochemical spectrum (indeed they function as feeding deterrents and poisons to other organisms within the plant itself), they are often associated with unpleasant side effects. In addition, these cholinesterase inhibiting alkaloids target only one system in a disorder, which is typified by multifactorial deficits. The present paper will look at the more benign terpene (such as Ginkgo biloba, Ginseng, Melissa officinalis (lemon balm) and Salvia lavandulaefolia (sage)) and phenolic (such as resveratrol) phytochemicals; arguing that they offer a safer alternative and that, as well as demonstrating efficacy in cholinesterase inhibition, these phytochemicals are able to target other salient systems such as cerebral blood flow, free radical scavenging, anti-inflammation, inhibition of amyloid-β neurotoxicity, glucoregulation and interaction with other neurotransmitters (such as γ-aminobutyric acid) and signalling pathways (e.g. via kinase enzymes).

Topics: Alkaloids; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Disease Models, Animal; Galantamine; Ginkgo biloba; Humans; Melissa; Panax; Phytochemicals; Plant Extracts; Resveratrol; Rivastigmine; Salvia officinalis; Stilbenes; Terpenes

Self-assembly of amyloid beta peptide (Aβ) into the neurotoxic oligomers followed by fibrillar aggregates is a defining characteristic of Alzheimer's disease (AD). Several lines of proposed hypotheses have suggested the mechanism of AD pathology, though the exact pathophysiological mechanism is not yet elucidated. The poor understanding of AD and multitude of adverse responses reported from the current synthetic drugs are the leading cause of failure in the drug development to treat or halt the progression of AD and mandate the search for safer and more efficient alternatives. A number of natural compounds have shown the ability to prevent the formation of the toxic oligomers and disrupt the aggregates, thus attracted much attention. Referable to the abundancy and multitude of pharmacological activities of the plant active constituents, biophenols that distinguish them from the other phytochemicals as a natural weapon against the neurodegenerative disorders. This review provides a critical assessment of the current literature on in vitro and in vivo mechanistic activities of biophenols associated with the prevention and treatment of AD. We have contended the need for more comprehensive approaches to evaluate the anti-AD activity of biophenols at various pathologic levels and to assess the current evidences. Consequently, we highlighted the various problems and challenges confronting the AD research, and offer recommendations for future research.

Topics: Alzheimer Disease; Animals; Antioxidants; Biomedical Research; Dietary Supplements; Flavonoids; Humans; Models, Neurological; Neurons; Neuroprotective Agents; Nootropic Agents; Oxidative Stress; Phenols; Phytochemicals; Plant Extracts; Research Design; Stilbenes

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

Imaging or tissue biomarker evidence has been introduced into the core diagnostic pathway for Alzheimer's disease (AD). PET using (18)F-labelled beta-amyloid PET tracers has shown promise for the early diagnosis of AD. However, most studies included only small numbers of participants and no consensus has been reached as to which radiotracer has the highest diagnostic accuracy. First, we performed a systematic review of the literature published between 1990 and 2014 for studies exploring the diagnostic accuracy of florbetaben, florbetapir and flutemetamol in AD. The included studies were analysed using the QUADAS assessment of methodological quality. A meta-analysis of the sensitivity and specificity reported within each study was performed. Pooled values were calculated for each radiotracer and for visual or quantitative analysis by population included. The systematic review identified nine studies eligible for inclusion. There were limited variations in the methods between studies reporting the same radiotracer. The meta-analysis results showed that pooled sensitivity and specificity values were in general high for all tracers. This was confirmed by calculating likelihood ratios. A patient with a positive ratio is much more likely to have AD than a patient with a negative ratio, and vice versa. However, specificity was higher when only patients with AD were compared with healthy controls. This systematic review and meta-analysis found no marked differences in the diagnostic accuracy of the three beta-amyloid radiotracers. All tracers perform better when used to discriminate between patients with AD and healthy controls. The sensitivity and specificity for quantitative and visual analysis are comparable to those of other imaging or biomarker techniques used to diagnose AD. Further research is required to identify the combination of tests that provides the highest sensitivity and specificity, and to identify the most suitable position for the tracer in the clinical pathway.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Case-Control Studies; Ethylene Glycols; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Stilbenes

Resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring phytochemical present in red wine, grapes, berries, chocolate and peanuts. Clinically, resveratrol has exhibited significant antioxidant, anti-inflammatory, anti-viral, and anti-cancer properties. Although resveratrol was first isolated in 1940, it was not until the last decade that it was recognised for its potential therapeutic role in reducing the risk of neurodegeneration, and Alzheimer's disease (AD) in particular. AD is the primary cause of progressive dementia. Resveratrol has demonstrated neuroprotective effects in several in vitro and in vivo models of AD. Apart from its potent antioxidant and anti-inflammatory roles, evidence suggests that resveratrol also facilitates non-amyloidogenic breakdown of the amyloid precursor protein (APP), and promotes removal of neurotoxic amyloid beta (Aβ) peptides, a critical step in preventing and slowing down AD pathology. Resveratrol also reduces damage to neuronal cells via a variety of additional mechanisms, most notably is the activation of NAD(+)-dependent histone deacetylases enzymes, termed sirtuins. However in spite of the considerable advances in clarifying the mechanism of action of resveratrol, it is unlikely to be effective as monotherapy in AD due to its poor bioavailability, biotransformation, and requisite synergism with other dietary factors. This review summarizes the relevance of resveratrol in the pathophysiology of AD. It also highlights why resveratrol alone may not be an effective single therapy, and how resveratrol coupled to other compounds might yet prove an effective therapy with multiple targets.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Humans; Neuroprotective Agents; Resveratrol; Stilbenes

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

The stilbene scaffold is a basic element for a number of biologically active natural and synthetic compounds, and it is considered as a privileged structure. Stilbenes exemplified by resveratrol, combretastatin A-4 and pterostilbene are of significant interest for drug research and development because of their potential in therapeutic and preventive application. Resveratrol, present in grapes and other food products, plays a role in the prevention of several human pathological processes and has been suggested as an anticancer agent. Moreover, recent evidence has revealed its potential effect on the aging process, diabetes and neurological dysfunction. Combretastatin A-4, from the bark of South African bush willow Combretum caffrum, also shows significant antitumor activity. Pterostilbene is closely related to resveratrol, sharing the same unique therapeutic potential as anti-inflammatory, antineoplastic and antioxidant agent. Therefore, research and development of stilbene-based medicinal chemistry have become rapidly evolving and increasingly active topics covering almost the whole range of therapeutic fields. In the present review, we provide an overview of the role of stilbenes in medicinal chemistry. In this context, we highlight the chemical methodologies adopted for the synthesis of stilbene derivatives, and outline the successful design of novel stilbene based hybrids in the field of cancer, Alzheimer's and other relevant diseases. This information may be useful in further design of stilbene-based molecules as new leads for the development of novel agents with clinical potential or as effective chemical probes to dissect biological processes.

Topics: Alzheimer Disease; Antineoplastic Agents, Phytogenic; Bibenzyls; Chemistry, Pharmaceutical; Drug Design; Humans; Neoplasms; Resveratrol; Stilbenes; Structure-Activity Relationship

Dietary interventions such as caloric restriction (CR) extend lifespan and health span. Recent data from animal and human studies indicate that CR slows down the aging process, benefits general health, and improves memory performance. Caloric restriction also retards and slows down the progression of different age-related diseases, such as Alzheimer's disease. However, the specific molecular basis of these effects remains unclear. A better understanding of the pathways underlying these effects could pave the way to novel preventive or therapeutic strategies. In this review, we will discuss the mechanisms and effects of CR on aging and Alzheimer's disease. A potential alternative to CR as a lifestyle modification is the use of CR mimetics. These compounds mimic the biochemical and functional effects of CR without the need to reduce energy intake. We discuss the effect of two of the most investigated mimetics, resveratrol and rapamycin, on aging and their potential as Alzheimer's disease therapeutics. However, additional research will be needed to determine the safety, efficacy, and usability of CR and its mimetics before a general recommendation can be proposed to implement them.

Topics: Aging; Alzheimer Disease; Biomimetics; Brain; Caloric Restriction; Energy Metabolism; Humans; Resveratrol; Sirolimus; Stilbenes

The suggested health effects (e.g., disease prevention) of dietary bioactive compounds such as resveratrol are challenging to prove in comparison to man-made drugs developed for therapeutic purposes. Dietary bioactive compounds have multiple cellular targets and therefore have a variety of biological effects. Extrapolating the biological effects of dietary compounds from in vitro and in vivo animal experiments to humans may lead to over- or under-estimation of the effect and role of these compounds. The present paper will discuss a few of these challenges and suggest directions for future research. Questions we address include: (1) Is the combinatorial effect of resveratrol and other compounds real? (2) What are the real and relevant doses of resveratrol after administration? and (3) Is it possible to estimate the preventive effect of resveratrol by clinical trials using standard experimental designs? The examples concerning resveratrol taken from the scientific literature are mainly from 2010 and later. The challenges pointed out in this review are similar to most naturally occurring bioactive compounds.

Topics: Alzheimer Disease; Animals; Antioxidants; Biological Availability; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Humans; Metabolic Diseases; Neoplasms; Phytochemicals; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes

Cellular autophagy is a major degradative pathway for clearance of aggregate-prone proteins and damaged organelles. It plays an important role in regulating cellular homeostasis, cell growth and development, and disease development. Dysfunctional autophagy contributes to the pathology of various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, in which specific pathological protein accumulation occurs. A growing body of evidence suggests that resveratrol plays a significantly role in the regulation of autophagy and clearance of pathological proteins. Resveratrol is a potential drug for neurodegenerative diseases therapy. This review focuses on the effects of resveratrol on cellular autophagy and clinical application in the control of neurodegenerative diseases.

Topics: Alzheimer Disease; Autophagy; Humans; Huntington Disease; Neurodegenerative Diseases; Parkinson Disease; Resveratrol; Stilbenes

The efficacy of 2, 3, 5, 4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) treatment on cognitive decline in individuals with Alzheimer's disease (AD) has not been investigated. Therefore, we systematically reviewed the effect of TSG on cognitive deficits in a rodent model of AD.. We identified eligible studies published from January 1980 to April 2015 by searching seven electronic databases. We assessed the study quality, evaluated the efficacy of TSG treatment, and performed a stratified meta-analysis and meta-regression analysis to assess the influence of study design on TSG efficacy.. Among a total of 381 publications, 18 fulfilled our inclusion criteria. The overall methodological quality of these studies was poor. The meta-analysis revealed a statistically significant benefit of TSG on acquisition memory (standardized mean difference [SMD] = -1.46 (95 % CI: -1.81 to -1.10, P < 0.0001) and retention memory (SMD =1.93 (95 % CI: 1.40 to 2.46, P < 0.0001) in experimental models of AD. The stratified analysis revealed a significantly higher effect size for both acquisition and retention memory in studies that used mixed sex models and a significantly higher effect size for acquisition memory in studies that used transgenic models.. Our meta-analysis highlights a significantly better treatment effect in rodent AD models that received TSG that in those that did not. These findings indicate a potential therapeutic role of TSG in AD therapy. However, additional well-designed and detailed experimental studies are needed to evaluate the safety of TSG.

Topics: Alzheimer Disease; Animals; Cognition; Disease Models, Animal; Glucosides; Humans; Mice; Rats; Stilbenes

Alzheimer's disease (AD) is a devastating disorder that strikes 1 in 10 Americans over the age of 65, and almost half of all Americans over 85 years old. The odds of an individual developing AD double every five years after the age of 65. While it has become increasingly common to meet heart attack or cancer survivors, there are no AD survivors. There is mounting evidence that dietary polyphenols, including resveratrol, may beneficially influence AD. Based on this consideration, several studies reported in the last few years were designed to validate sensitive and reliable translational tools to mechanistically characterize brain bioavailable polyphenols as disease-modifying agents to help prevent the onset of AD dementia and other neurodegenerative disorders. Several research groups worldwide with expertise in AD, plant biology, nutritional sciences, and botanical sciences have reported very high quality studies that ultimately provided the necessary information showing that polyphenols and their metabolites, which come from several dietary sources, including grapes, cocoa etc., are capable of preventing AD. The ultimate goal of these studies was to provide novel strategies to prevent the disease even before the onset of clinical symptoms. The studies discussed in this review article provide support that the information gathered in the last few years of research will have a major impact on AD prevention by providing vital knowledge on the protective roles of polyphenols, including resveratrol. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.

Topics: Alzheimer Disease; Amyloid; Animals; Humans; Polyphenols; Resveratrol; Stilbenes; Vitis

Molecules of the plant world are proving their effectiveness in countering, slowing down, and regressing many diseases. The resveratrol for its intrinsic properties related to its stilbene structure has been proven to be a universal panacea, especially for a wide range of neurodegenerative diseases. This paper evaluates (in vivo and in vitro) the various molecular targets of this peculiar polyphenol and its ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. What emerges is that, in the deep heterogeneity of the pathologies evaluated, resveratrol through a convergence on the protein targets is able to give therapeutic responses in neuronal cells deeply diversified not only in morphological structure but especially in their function performed in the anatomical district to which they belong.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Humans; Huntington Disease; Mitochondria; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease; Resveratrol; Stilbenes

Peanuts are important dietary food source of resveratrol with potent antioxidant properties implicated in reducing risk of cancer, cardiovascular and Alzheimer's disease, and delaying aging. Resveratrol is a naturally occurring stilbene phytoalexin phenolic compound produced in response to a variety of biotic and abiotic stresses. This paper is a review of trans-resveratrol and related stilbenes from peanuts--their chemical structures, mechanisms for their biosynthesis, and concentrations in comparison with other major food sources. It will also discuss trans-resveratrol's absorption, bioavailability, and major health benefits; processes to enhance their biosynthesis in peanuts by biotic and abiotic stresses; process optimization for enhanced levels in peanuts and their potential food applications; and methods used for its extraction and analysis.

Topics: Alzheimer Disease; Antioxidants; Arachis; Biological Availability; Cardiovascular Diseases; Diet; Humans; Neoplasms; Resveratrol; Stilbenes

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

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

Alzheimer's disease (AD) is the most common cause of dementia, but there is no effective therapy till now. The pathogenic mechanisms of AD are considerably complex, including Aβ accumulation, tau protein phosphorylation, oxidative stress, and inflammation. Exactly, resveratrol, a polyphenol in red wine and many plants, is indicated to show the neuroprotective effect on mechanisms mostly above. Recent years, there are numerous researches about resveratrol acting on AD in many models, both in vitro and in vivo. However, the effects of resveratrol are limited by its pool bioavailability; therefore researchers have been trying a variety of methods to improve the efficiency. This review summarizes the recent studies in cell cultures and animal models, mainly discusses the molecular mechanisms of the neuroprotective effects of resveratrol, and thus investigates the therapeutic potential in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Neuroprotective Agents; Oxidative Stress; Resveratrol; Stilbenes

Alzheimer's disease (AD) is the most prevalent form of dementia and affects approximately 24 million people worldwide. One possible approach for the treatment of this disease is the restoration of the level of acetylcholine (ACh) through the inhibition of acetylcholinesterase (AChE) with reversible inhibitors. Naturally occurring alkaloids are an important source of AChE inhibitors. Galantamine and huperzine A have been used for the clinical treatment of AD patients. In this review, we summarise the natural products and their derivatives that were reported to act as AChE inhibitors for the treatment of AD in 2010-2013. Several characteristics were summarised from the literature results: 1) Amongst all of the natural products with AChE inhibitory activity, alkaloids appear to be the most promising compound class. 2) Coumarins, flavonoids, stilbenes, and other natural products are also important AChE inhibitors from natural products. Among these inhibitors, 146 (IC50 = 0.573 µM) was identified as the most potent AChE inhibitor. 3) A coumarin derivative (117, IC50 = 0.11 nM) exhibited more than 100-fold superior activity compared with the reference drug donepezil hydrochloride (IC50 = 14 nM). In conclusion, natural products and their derivatives are promising leads for the development of new drugs for the future treatment of AD.

Topics: Acetylcholinesterase; Alkaloids; Alzheimer Disease; Biological Products; Cholinesterase Inhibitors; Coumarins; Drug Discovery; Flavonoids; Humans; Nootropic Agents; Stilbenes; Structure-Activity Relationship

Alzheimer's disease (AD) is the most common cause of dementia, being responsible for high healthcare costs and familial hardships. Despite the efforts of researchers, no treatment able to delay or stop AD progress exists. Currently, the available treatments are only symptomatic, cholinesterase inhibitors being the most widely used drugs. Here we describe several natural compounds with anticholinesterase (acetylcholinesterase and butyrylcholinesterase) activity and also some synthetic compounds whose structures are based on those of natural compounds.. Galantamine and rivastigmine are two cholinesterase inhibitors used in therapeutics: galantamine is a natural alkaloid that was extracted for the first time from Galanthus nivalis L., while rivastigmine is a synthetic alkaloid, the structure of which is modelled on that of natural physostigmine. Alkaloids include a high number of compounds with anticholinesterases activity at the submicromolar range. Quinones and stilbenes are less well studied regarding cholinesterase inhibition, although some of them, such as sargaquinoic acid or (+)-α-viniferin, show promising activity. Among flavonoids, flavones and isoflavones are the most potent compounds. Xanthones and monoterpenes are generally weak cholinesterase inhibitors.. Nature is an almost endless source of bioactive compounds. Several natural compounds have anticholinesterase activity and others can be used as leader compounds for the synthesis of new drugs.

Topics: Alkaloids; Alzheimer Disease; Biological Products; Cholinesterase Inhibitors; Cholinesterases; Coumarins; Flavonoids; Humans; Quinones; Stilbenes; Xanthones

The polyphenolic compound resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring phytochemical which has been found in more than 70 plant species, including herbs and human food products such as grapes, berries, and peanuts. Resveratrol was first isolated in 1940; however, little attention was paid to it until its benefits in coronary heart disease were studied in 1992. Since then, increasing evidence has indicated that resveratrol may be useful in treating cardiovascular diseases, cancers, pain, inflammation, tissue injury, and in reducing the risk of neurodegenerative disorders, especially Alzheimer's disease (AD). AD is characterized by a progressive dementia, and is one of the most common neurodegenerative disorders in the elderly. It has been reported that resveratrol exhibits neuroprotective benefits in animal models of AD. Resveratrol promotes the non-amyloidogenic cleavage of the amyloid precursor protein, enhances clearance of amyloid beta-peptides, and reduces neuronal damage. Despite the effort spent trying to understand the mechanisms by which resveratrol functions, the research work in this field is still incomplete. Many concerns such as bioavailability, biotransformation, synergism with other dietary factors, and risks inherent to its possible pro-oxidant activities still need to be addressed. This review summarizes and discusses the neuroprotective effects of resveratrol on AD, and their potential mechanisms.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Humans; Neurons; Neuroprotective Agents; Resveratrol; Stilbenes

Mild cognitive impairment is characterized by a decline in cognitive performance without interference with activities of daily living. The amnestic subtype of mild cognitive impairment progresses to Alzheimer's disease at a rate of 10-15% per year and in the majority the neuropathology is intermediate between the neuropathological changes of typical ageing and Alzheimer's disease. Amyloid deposition occurs over a decade before the development of noticeable cognitive symptoms in a continuous process that starts in healthy elderly individuals. Newly developed PET amyloid imaging agents provide noninvasive biomarkers for the early in vivo detection of Alzheimer's pathology in healthy elderly individuals and those with mild cognitive impairment. Exclusion of amyloid pathology should allow a more accurate prognosis to be given and ensure appropriate recruitment into clinical trials testing the efficacy of new putative antiamyloid agents at an earlier disease stage. The development of (18)F-labelled amyloid imaging agents has increased the availability of this new technology for clinical and research use since they can be used in PET centres where a cyclotron and radiochemistry are not available. This review discusses the role of PET imaging for assessing the amyloid load in cognitively normal elderly subjects and subjects with mild cognitive impairment at risk of conversion to Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Humans; Plaque, Amyloid; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; Stilbenes; Thiazoles

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

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

Stilbenoid compounds consist of a family of resveratrol derivatives. They have demonstrated promising activities in vitro and in vivo that indicate they may be useful in the prevention of a wide range of pathologies, such as cardiovascular diseases and cancers, as well have anti-aging effects. More recently stilbenoid compounds have shown promise in the treatment and prevention of neurodegenerative disorders, such as Huntington's, Parkinson's, and Alzheimer's diseases. This paper primarily focuses on the impact of stilbenoids in Alzheimer's disease and more specifically on the inhibition of β-amyloid peptide aggregation.

Topics: Alzheimer Disease; Animals; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Resveratrol; Stilbenes

Class III histone deacetylases (sirtuins) are becoming increasingly recognized as important epigenetic drug targets in cancer and metabolic disorders. As key regulators involved in numerous cellular signalling pathways, sirtuins are also emerging as potential targets in various neurodegenerative diseases such as Alzheimer, Parkinson's disease and others, thus suggesting modulation of sirtuin activity could provide an interesting and novel therapeutic option. In particular, much attention has been raised by neuroprotective effects attributed to SIRT1 activation due to genetically induced sirtuin overexpression or administration of resveratrol, a natural compound found in the skin of red grapes and also in wine. Similarly, also sirtuin inhibitors display benefits in various neuropathologic disease models. In light of the growing interest in sirtuin modulation and with regard to the lack of conclusive data on small molecule activators of sirtuins this review recapitulates the known facts about sirtuins and their relevance in neurodegenerative diseases.

Topics: Alzheimer Disease; Enzyme Inhibitors; Epigenesis, Genetic; Humans; Neurodegenerative Diseases; Parkinson Disease; Resveratrol; Sirtuins; Stilbenes; Up-Regulation

PET imaging of amyloid-β has recently emerged as a valuable biomarker to support the in vivo diagnosis of Alzheimer's disease (AD). So far, however, no tracer is available suitable for general clinical routine application. Florbetaben is a promising 18F-labeled amyloid-β-targeted PET tracer currently in Phase 2/3 clinical development. This review provides an overview on the current knowledge and future research activities on florbetaben. Recently, the first worldwide multi-center trial to test the diagnostic performance of amyloid-β PET in AD was conducted with this tracer. From this trial, a sensitivity and specificity of 80 and 91% in the discrimination between patients with probable AD and age-matched healthy controls was reported. Ongoing florbetaben PET trials deal with correlating the in vivo PET signal to post mortem histopathology evaluation, and with investigating the value of the tracer to predict progression to AD at the stage of mild cognitive impairment. The preclinical and clinical data currently available verify florbetaben as a safe and efficacious PET tracer suitable for detection of amyloid-β deposition in the brain. The results of the ongoing trials will contribute to current knowledge on the characteristics of florbetaben, and will help to determine the future potential of florbetaben PET imaging as a visual adjunct to supplement the routine clinical "AD diagnostic toolbox".

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Humans; Positron-Emission Tomography; Stilbenes

Neurological disease, and in particular neurodegenerative diseases, cause significant burdens on both patient and healthcare costs. Despite extensive research, treatment options for patients with these conditions remain limited, and generally, only provide modest symptomatic relief. Aberrant epigenetic post-translational modifications of proteins are emerging as important elements in the pathogenesis of neurological disease. Using Alzheimer's disease and Huntington's disease as examples in the following article, some of latest data linking both the histone code and the various proteins that regulate this code to the pathogenesis of neurological disease are discussed. The current evidence suggesting that pharmacologically targeting one such family, the histone deacetylases, may be of potential benefit in the treatment of such diseases is also discussed. Finally, some of the potential mechanisms to specifically target these proteins within the neurological setting are discussed.

Topics: Alzheimer Disease; Butylamines; Cell Differentiation; Endoplasmic Reticulum Stress; Epigenesis, Genetic; Histone Code; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Huntington Disease; Hydroxamic Acids; Neurons; Phenylbutyrates; Protein Processing, Post-Translational; Resveratrol; Stilbenes; Valproic Acid; Vorinostat

Sirt1, a mammalian member of the sirtuin gene family, holds great potential for promoting longevity, preventing against disease and increasing cell survival. For example, studies suggest that the beneficial impact of caloric restriction in promoting longevity and cellular function may be mediated, in part, by Sirt1 through mechanisms involving PGC-1alpha, which plays important role in the regulation of cellular metabolism and inflammatory and antioxidant responses. Sirt1 may also interfere with mechanisms implicated in pathological disorders. We will present recent evidence indicating that Sirt1 may protect against Alzheimer's disease by interfering with the generation of beta-amyloid peptides. We will discuss Sirt1 as a potential novel target, in addition to the development of Sirt1 activators for the prevention and treatment of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloidosis; Animals; Caloric Restriction; Humans; Longevity; NAD; Resveratrol; Sirtuin 1; Stilbenes

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

Although a battery of neuropsychological tests is often used in making a clinical diagnosis of Alzheimer's disease (AD), definitive diagnosis still relies on pathological evaluation at autopsy. The identification of AD biomarkers may allow for a less invasive and more accurate diagnosis as well as serve as a predictor of future disease progression and treatment response. Importantly, biomarkers may also allow for the identification of individuals who are already developing the underlying pathology of AD such as plaques and tangles yet who are not yet demented, i.e. "preclinical" AD. Attempts to identify biomarkers have included fluid and imaging studies, with a number of candidate markers showing significant potential. More recently, better reagent availability and novel methods of assessment have further spurred the search for biomarkers of AD. This review will discuss promising fluid and imaging markers to date.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Benzoxazoles; Biomarkers; Brain; Cerebrovascular Circulation; Humans; Isoprostanes; Microglia; Nitriles; Protease Nexins; Radiography; Receptors, Cell Surface; Regional Blood Flow; Stilbenes; tau Proteins; Thiazoles

Currently, the development of radiotracers for in vivo imaging of beta-amyloid plaques in Alzheimer's disease (AD) brains is an important, active area of molecular imaging. Postmortem brains of AD patients reveal neuropathologic features: the presence of beta-amyloid plaques and neurofibrillary tangles, which contain beta-amyloid peptides and highly phosphorylated tau proteins. Increases in the concentration of beta-amyloid in the course of the disease lead to changes in AD brains. Thus, when used in combination with positron-emission tomography/single-photon emission computed tomography (PET/SPECT), beta-amyloid imaging agents could serve as surrogate markers for the early diagnosis and neuropathogenetic studies of AD. Furthermore, quantitative evaluation of beta-amyloid plaques in the brain could facilitate the evaluation of the efficacy of antiamyloid therapies that are currently being investigated. This paper reviews our research on the development of PET/SPECT imaging agents for in vivo detection of beta-amyloid plaques in Alzheimer's brains.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzofurans; Brain; Flavonoids; Humans; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

Several epidemiological studies indicate that moderate consumption of red wine is associated with a lower incidence of dementia and Alzheimer's disease. Red wine is enriched in antioxidant polyphenols with potential neuroprotective activities. Despite scepticism concerning the bioavailability of these polyphenols, in vivo data have clearly demonstrated the neuroprotective properties of the naturally occurring polyphenol resveratrol in rodent models for stress and diseases. Furthermore, recent work in cell cultures and animal models has shed light on the molecular mechanisms potentially involved in the beneficial effects of resveratrol intake against the neurodegenerative process in Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Antioxidants; Dementia; Flavonoids; Humans; Nerve Degeneration; Phenols; Polyphenols; Resveratrol; Stilbenes; Wine

Resveratrol, an antioxidant polyphenol from red wine, has been the subject of intense interest in recent years due to a range of unique anti-aging properties. These include cardiovascular benefits via increased nitric oxide production, down-regulation of vasoactive peptides, lowered levels of oxidized low-density lipoprotein, and cyclooxygenase inhibition; possible benefits on Alzheimer's disease by breakdown of beta-amyloid and direct effects on neural tissues; phytohormonal actions; anticancer properties via modulation of signal transduction, which translates into anti-initiation, antipromotion, and antiprogression effects; antimicrobial effects; and sirtuin activation, which is believed to be involved in the caloric restriction-longevity effect. Here we report a resveratrol-based skin care formulation, with 17 times greater antioxidant activity than idebenone. The role of resveratrol in prevention of photoaging is reviewed and compared with other antioxidants used in skin care products.

Topics: Aging; Alzheimer Disease; Animals; Antioxidants; Heart Diseases; Humans; Resveratrol; Sirtuins; Skin Aging; Stilbenes; Wine

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by severe cognitive impairment that ultimately leads to death. Current drugs used in AD are acetylcholinesterase inhibitors and antagonists to the NMDA receptors. These drugs may only slightly improve cognitive functions but have only very limited impact on the clinical course of the disease. In the past several years, based on in vitro and in vivo studies in laboratory animals, natural antioxidants, such as resveratrol, curcumin and acetyl-L-carnitine have been proposed as alternative therapeutic agents for AD. An increasing number of studies demonstrated the efficacy of primary antioxidants, such as polyphenols, or secondary antioxidants, such as acetylcarnitine, to reduce or to block neuronal death occurring in the pathophysiology of this disorder. These studies revealed that other mechanisms than the antioxidant activities could be involved in the neuroprotective effect of these compounds. This paper discusses the evidence for the role of acetylcarnitine in modulating redox-dependent mechanisms leading to the upregulation of vitagenes. Furthermore, future development of novel antioxidant drugs targeted to the mitochondria should result in effectively slowing disease progression. The association with new drug delivery systems may be desirable and useful for the therapeutic use of antioxidants in human neurodegenerative diseases.

Topics: Acetylcarnitine; Alzheimer Disease; Animals; Antioxidants; Cholinesterase Inhibitors; Humans; Neuroprotective Agents; Oxidative Stress; Resveratrol; Stilbenes

Resveratrol, a red wine polyphenol, is known to protect against cardiovascular diseases and cancers, as well as to promote antiaging effects in numerous organisms. It also modulates pathomechanisms of debilitating neurological disorders, such as strokes, ischemia, and Huntington's disease. The role of resveratrol in Alzheimer's disease is still unclear, although some recent studies on red wine bioactive compounds suggest that resveratrol modulates multiple mechanisms of Alzheimer's disease pathology. Emerging literature indicates that mechanisms of aging and Alzheimer's disease are intricately linked and that these mechanisms can be modulated by both calorie restriction regimens and calorie restriction mimetics, the prime mediator of which is the SIRT1 protein, a human homologue of yeast silent information regulator (Sir)-2, and a member of NAD+-dependent histone deacetylases. Calorie restriction regimens and calorie restriction-mimetics trigger sirtuins in a wide variety of organisms, ranging from bacteria to mouse. In a mouse model of Huntington's disease, resveratrol-induced SIRT1 was found to protect neurons against ployQ toxicity and in Wallerian degeneration slow mice, resveratrol was found to protect the degeneration of neurons from axotomy, suggesting that resveratrol may possess therapeutic value to neuronal degeneration. This paper mainly focuses on the role of resveratrol in modulating AD pathomechanisms.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Brain; Caloric Restriction; Humans; Nerve Degeneration; Reactive Oxygen Species; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes

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

Magnetic resonance-guided focused ultrasound in combination with intravenously injected microbubbles has been shown to transiently open the blood-brain barrier, and reduce beta-amyloid and tau pathology in animal models of Alzheimer's disease. Here, we used focused ultrasound to open the blood-brain barrier in five patients with early to moderate Alzheimer's disease in a phase I safety trial. In all patients, the blood-brain barrier within the target volume was safely, reversibly, and repeatedly opened. Opening the blood-brain barrier did not result in serious clinical or radiographic adverse events, as well as no clinically significant worsening on cognitive scores at three months compared to baseline. Beta-amyloid levels were measured before treatment using [

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biological Transport; Blood-Brain Barrier; Brain; Female; Humans; Magnetic Resonance Imaging; Male; Microbubbles; Middle Aged; Positron Emission Tomography Computed Tomography; Prospective Studies; Psychometrics; Stilbenes; Ultrasonography

Of 57 individuals diagnosed with Alzheimer's disease (AD) in a phase III study, 13 (23%) had amyloid-β (Aβ) levels on postmortem histopathology that did not explain the dementia. Based on postmortem histopathology, a wide range of different non-AD conditions was identified, including frontotemporal dementia, hippocampal sclerosis, and dementia with Lewy bodies. Of the histopathologically Aβ negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Aβ in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite standardized uptake value ratios. Thus, florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative disorders by reliably excluding Aβ pathology.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes

Treatment of mild-moderate Alzheimer's disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily living (ADL) scores.. For this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42 <600 ng/ml (biomarker-confirmed AD) at baseline (N = 19 resveratrol-treated and N = 19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples.. Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not alter tau levels.. Collectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders.. ClinicalTrials.gov NCT01504854.

Topics: Activities of Daily Living; Adaptive Immunity; Alzheimer Disease; Amyloid beta-Peptides; Anti-Inflammatory Agents, Non-Steroidal; Chemokine CCL5; Cognition Disorders; Cytokines; Double-Blind Method; Encephalitis; Female; Fibroblast Growth Factor 2; Follow-Up Studies; Humans; Male; Matrix Metalloproteinase 9; Mental Status Schedule; Peptide Fragments; Resveratrol; Stilbenes; tau Proteins

Neocortical atrophy reduces PET signal intensity, potentially affecting the diagnostic efficacy of β-amyloid (Aβ) brain PET imaging. This study investigated whether partial-volume effect correction (PVEC), adjusting for this atrophy bias, improves the accuracy of (18)F-florbetaben Aβ PET.. We analyzed (18)F-florbetaben PET and MRI data obtained from 3 cohorts. The first was 10 patients with probable Alzheimer disease (AD) and 10 age-matched healthy controls (HCs), the second was 31 subjects who underwent in vivo imaging and postmortem histopathology for Aβ plaques, and the third was 5 subjects who underwent PET and MRI at baseline and 1 y later. The imaging data were coregistered and segmented. PVEC was performed using the voxel-based modified Müller-Gärtner method (PVELab, SPM8). From the PET data, regional and composite SUV ratios (SUVRs) with and without PVEC were obtained. In the MRI data, mesial temporal lobe atrophy was determined by the Scheltens mesial temporal atrophy scale and gray matter volumes by voxel-based morphometry.. In cohort 1, PVEC increased the effect on AD-versus-HC discrimination from a Cohen d value of 1.68 to 2.0 for composite SUVRs and from 0.04 to 1.04 for mesial temporal cortex SUVRs. The PVEC-related increase in mesial temporal cortex SUVR correlated with the Scheltens score (r = 0.84, P < 0.001), and that of composite SUVR correlated with the composite gray matter volume (r = -0.75, P < 0.001). In cohort 2, PVEC increased the correlation coefficient between mesial temporal cortex SUVR and histopathology score for Aβ plaque load from 0.28 (P = 0.09) to 0.37 (P = 0.03). In cohort 3, PVEC did not affect the composite SUVR dynamics over time for the Aβ-negative subject. This finding was in contrast to the 4 Aβ-positive subjects, in 2 of whom PVEC changed the composite SUVR dynamics.. The influence of PVEC on (18)F-florbetaben PET data is associated with the degree of brain atrophy. Thus, PVEC increases the ability of (18)F-florbetaben PET to discriminate between AD patients and HCs, to detect Aβ plaques in the atrophic mesial temporal cortex, and potentially to evaluate changes in brain Aβ load over time. As such, the use of PVEC should be considered for quantitative (18)F-florbetaben PET scans, especially in assessing patients with brain atrophy.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Cerebral Cortex; Cohort Studies; Female; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Magnetic Resonance Imaging; Male; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes; Temporal Lobe

We assessed the clinical utility of β-amyloid (Aβ) imaging with (18)F-florbetaben (FBB) in mild cognitive impairment (MCI) by evaluating its prognostic accuracy for progression to Alzheimer's disease (AD), comparing semiquantitative with visual scan assessment, and exploring the relationships among Aβ, hippocampal volume (HV) and memory over time.. 45 MCI underwent FBB positron emission tomography, MRI and neuropsychological assessment at baseline and 2 years and clinical follow-up at 4 years. Positive FBB (FBB+), defined by a cortical to cerebellar cortex standardised uptake value ratio (SUVR) ≥ 1.45, was compared with visual assessment by five readers. Amnestic MCI (aMCI) was defined by a composite episodic memory (EM) Z-score of <-1.5.. At baseline, 24 (53%) MCI were FBB+. Majority reads agreed with SUVR classification (κ 0.96). In 2 years, 18 (75%) FBB+ progressed to AD compared with 2 (9.5%) FBB-, yielding a predictive accuracy of 83% (95% CI 61% to 94%). Four FBB- developed non-AD dementia. Predictive accuracies of HV (58% (95% CI 42% to 73%)) and aMCI status (73% (95% CI 58% to 81%)) were lower. Combinations did not improve accuracy. By 4 years, 21 (87.5%) FBB+ had AD whereas 5 (24%) FBB- had non-AD dementia yielding a predictive accuracy of 94% (95% CI 74% to 99%). While the strong baseline association between FBB SUVR and EM declined over 2 years, the association between EM and HV became stronger. FBB SUVR increased 2.2%/year in FBB+ with no change in FBB-.. (18)F-florbetaben Aβ imaging facilitates accurate detection of prodromal AD. As neurodegeneration progresses, and in contrast with the early stages of the disease, hippocampal atrophy and not Aβ, seems to drive memory decline.. NCT01138111.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Disease Progression; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Memory Disorders; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Stilbenes

Evaluation of brain β-amyloid by positron emission tomography (PET) imaging can assist in the diagnosis of Alzheimer disease (AD) and other dementias.. Open-label, nonrandomized, multicenter, phase 3 study to validate the (18)F-labeled β-amyloid tracer florbetaben by comparing in vivo PET imaging with post-mortem histopathology.. Brain images and tissue from 74 deceased subjects (of 216 trial participants) were analyzed. Forty-six of 47 neuritic β-amyloid-positive cases were read as PET positive, and 24 of 27 neuritic β-amyloid plaque-negative cases were read as PET negative (sensitivity 97.9% [95% confidence interval or CI 93.8-100%], specificity 88.9% [95% CI 77.0-100%]). In a subgroup, a regional tissue-scan matched analysis was performed. In areas known to strongly accumulate β-amyloid plaques, sensitivity and specificity were 82% to 90%, and 86% to 95%, respectively.. Florbetaben PET shows high sensitivity and specificity for the detection of histopathology-confirmed neuritic β-amyloid plaques and may thus be a valuable adjunct to clinical diagnosis, particularly for the exclusion of AD.. ClinicalTrials.govNCT01020838.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Aniline Compounds; Brain; Cohort Studies; Diagnosis; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Psychiatric Status Rating Scales; Radiography; ROC Curve; Stilbenes

A randomized, placebo-controlled, double-blind, multicenter 52-week phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease (AD) examined its safety and tolerability and effects on biomarker (plasma Aβ40 and Aβ42, CSF Aβ40, Aβ42, tau, and phospho-tau 181) and volumetric MRI outcomes (primary outcomes) and clinical outcomes (secondary outcomes).. Participants (n = 119) were randomized to placebo or resveratrol 500 mg orally once daily (with dose escalation by 500-mg increments every 13 weeks, ending with 1,000 mg twice daily). Brain MRI and CSF collection were performed at baseline and after completion of treatment. Detailed pharmacokinetics were performed on a subset (n = 15) at baseline and weeks 13, 26, 39, and 52.. Resveratrol and its major metabolites were measurable in plasma and CSF. The most common adverse events were nausea, diarrhea, and weight loss. CSF Aβ40 and plasma Aβ40 levels declined more in the placebo group than the resveratrol-treated group, resulting in a significant difference at week 52. Brain volume loss was increased by resveratrol treatment compared to placebo.. Resveratrol was safe and well-tolerated. Resveratrol and its major metabolites penetrated the blood-brain barrier to have CNS effects. Further studies are required to interpret the biomarker changes associated with resveratrol treatment.. This study provides Class II evidence that for patients with AD resveratrol is safe, well-tolerated, and alters some AD biomarker trajectories. The study is rated Class II because more than 2 primary outcomes were designated.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Double-Blind Method; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Resveratrol; Stilbenes

To evaluate the performance characteristics of florbetapir F18 positron emission tomography (PET) in patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy control subjects (HCs).. Florbetapir PET was acquired in 184 subjects (45 AD patients, 60 MCI patients, and 79 HCs) within a multicenter phase 2 study. Amyloid burden was assessed visually and quantitatively, and was classified as positive or negative.. Florbetapir PET was rated visually amyloid positive in 76% of AD patients, 38% of MCI patients, and 14% of HCs. Eighty-four percent of AD patients, 45% of MCI patients, and 23% of HCs were classified as amyloid positive using a quantitative threshold. Amyloid positivity and mean cortical amyloid burden were associated with age and apolipoprotein E ε4 carrier status.. : The data are consistent with expected rates of amyloid positivity among individuals with clinical diagnoses of AD and MCI, and indicate the potential value of florbetapir F18 PET as an adjunct to clinical diagnosis.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloidogenic Proteins; Aniline Compounds; Apolipoprotein E4; Cognitive Dysfunction; Female; Fluorine Radioisotopes; Humans; Male; Mental Status Schedule; Middle Aged; Positron-Emission Tomography; Stilbenes

Amyloid imaging with (18)F-labelled radiotracers will allow widespread use of this technique, facilitating research, diagnosis and therapeutic development for Alzheimer's disease (AD). The purpose of this analysis was to compare data on cortical Aβ deposition in subjects who had undergone both (11)C-PiB (PiB) and (18)F-florbetaben (FBB) PET imaging.. We identified ten healthy elderly controls (HC) and ten patients with AD who had undergone PET imaging after intravenous injection of 370 MBq of PiB and 300 MBq of FBB under separate research protocols. PiB and FBB images were coregistered so that placement of regions of interest was identical on both scans and standard uptake value ratios (SUVR) using the cerebellar cortex as reference region were calculated between 40 and 70 min and between 90 and 110 min after injection for PiB and FBB, respectively.. Significantly higher SUVR values (p < 0.0001) in most cortical areas were observed in AD patients when compared with HC with both radiotracers. Global SUVR values in AD patients were on average 75% higher than in HC with PiB and 56% higher with FBB. There was an excellent linear correlation between PiB and FBB global SUVR values (r = 0.97, p < 0.0001) with similar effect sizes for distinguishing AD from HC subjects for both radiotracers (Cohen's d 3.3 for PiB and 3.0 for FBB).. FBB, while having a narrower dynamic range than PiB, clearly distinguished HC from AD patients, with a comparable effect size. FBB seems a suitable (18)F radiotracer for imaging AD pathology in vivo.

Topics: Aged; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Stilbenes; Thiazoles

[(11)C]PIB and [(18)F]FDDNP are PET tracers for in vivo detection of the neuropathology underlying Alzheimer's disease (AD). [(18)F]FDG is a glucose analogue and its uptake reflects metabolic activity. The purpose of this study was to examine longitudinal changes in these tracers in patients with AD or mild cognitive impairment (MCI) and in healthy controls.. Longitudinal, paired, dynamic [(11)C]PIB and [(18)F]FDDNP (90 min each) and static [(18)F]FDG (15 min) PET scans were obtained in 11 controls, 12 MCI patients and 8 AD patients. The mean interval between baseline and follow-up was 2.5 years (range 2.0-4.0 years). Parametric [(11)C]PIB and [(18)F]FDDNP images of binding potential (BP(ND)) and [(18)F]FDG standardized uptake value ratio (SUVr) images were generated.. A significant increase in global cortical [(11)C]PIB BP(ND) was found in MCI patients, but no changes were observed in AD patients or controls. Subsequent regional analysis revealed that this increase in [(11)C]PIB BP(ND) in MCI patients was most prominent in the lateral temporal lobe (p < 0.05). For [(18)F]FDDNP, no changes in global BP(ND) were found. [(18)F]FDG uptake was reduced at follow-up in the AD group only, especially in frontal, parietal and lateral temporal lobes (all p < 0.01). Changes in global [(11)C]PIB binding (ρ = -0.42, p < 0.05) and posterior cingulate [(18)F]FDG uptake (ρ = 0.54, p < 0.01) were correlated with changes in Mini-Mental-State Examination score over time across groups, whilst changes in [(18)F]FDDNP binding (ρ = -0.18, p = 0.35) were not.. [(11)C]PIB and [(18)F]FDG track molecular changes in different stages of AD. We found increased amyloid load in MCI patients and progressive metabolic impairment in AD patients. [(18)F]FDDNP seems to be less useful for examining disease progression.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Case-Control Studies; Cognitive Dysfunction; Female; Humans; Longitudinal Studies; Male; Middle Aged; Nitriles; Positron-Emission Tomography; Stilbenes; Thiazoles; Time Factors

Complementing clinical findings with those generated by biomarkers--such as β-amyloid-targeted positron emission tomography (PET) imaging--has been proposed as a means of increasing overall accuracy in the diagnosis of Alzheimer's disease (AD). Florbetaben ([(18)F]BAY 94-9172) is a novel β-amyloid PET tracer currently in global clinical development. We present the results of a proof of mechanism study in which the diagnostic efficacy, pharmacokinetics, safety and tolerability of florbetaben were assessed. The value of various quantitative parameters derived from the PET scans as potential surrogate markers of cognitive decline was also investigated.. Ten patients with mild-moderate probable AD (DSM-IV and NINCDS-ADRDA criteria) and ten age-matched (≥ 55 years) healthy controls (HCs) were administered a single dose of 300 MBq florbetaben, which contained a tracer mass dose of < 5 μg. The 70-90 min post-injection brain PET data were visually analysed by three blinded experts. Quantitative assessment was also performed via MRI-based, anatomical sampling of predefined volumes of interest (VOI) and subsequent calculation of standardized uptake value (SUV) ratios (SUVRs, cerebellar cortex as reference region). Furthermore, single-case, voxelwise analysis was used to calculate individual "whole brain β-amyloid load".. Visual analysis of the PET data revealed nine of the ten AD, but only one of the ten HC brains to be β-amyloid positive (p = 0.001), with high inter-reader agreement (weighted kappa ≥ 0.88). When compared to HCs, the neocortical SUVRs were significantly higher in the ADs (with descending order of effect size) in frontal cortex, lateral temporal cortex, occipital cortex, anterior and posterior cingulate cortices, and parietal cortex (p = 0.003-0.010). Voxel-based group comparison confirmed these differences. Amongst the PET-derived parameters, the Statistical Parametric Mapping-based whole brain β-amyloid load yielded the closest correlation with the Mini-Mental State Examination scores (r = -0.736, p < 0.001), following a nonlinear regression curve. No serious adverse events or other safety concerns were seen.. These results indicate florbetaben to be a safe and efficacious β-amyloid-targeted tracer with favourable brain kinetics. Subjects with AD could be easily differentiated from HCs by both visual and quantitative assessment of the PET data. The operator-independent, voxel-based analysis yielded whole brain β-amyloid load which appeared valuable as a surrogate marker of disease severity.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Case-Control Studies; Diagnosis, Differential; Feasibility Studies; Female; Humans; Image Processing, Computer-Assisted; Kinetics; Male; Middle Aged; Positron-Emission Tomography; Precision Medicine; Safety; Stilbenes

The stilbene-rich acetone fraction in high yield (6.6 %, PEAS) of Passiflora edulis Sims was prepared and evaluated for neuroprotective activity in murine Alzheimer's disease model induced by aluminum chloride and D-galactose. The phytochemical and HPLC-DAD-MS analysis of the polyphenolic stilbene-rich acetone fraction showed that it contained different stilbenes including trans-piceatannol, scirpusins A-B and cassigarol E. The total phenolic content (TPC) of PEAS was 413.87±1.71 mg GAE eqv/g. The neuroprotective activity of PEAS is typically presented in the Morris water maze-reference Spatial Memory test, where the Alzheimer's mice treated at 100 mg/kg (Alz-ED1) and 200 mg/kg (Alz-ED2) spent less than 47 % and 66 % of the time, respectively, than the Alzheimer's model mice (Alz). Two simple stilbenes, trans-piceatannol and trans-resveratrol, showed selectively inhibitory activity in silico against acetylcholinesterase (AChE). Two stilbene dimers, cassigarol E and scirpusin A, exhibited low nanomolar inhibitory potential against AChE and butyrylcholinesterase (BChE), significantly lower than those of the positive control, donepezil and tacrine. These findings suggest that the stilbenes from P. edulis seeds, particularly the stilbene dimers, warrant further investigation as potential neuroprotective candidates in the prevention of cognitive deficits associated with Alzheimer's disease.

Topics: Acetone; Acetylcholinesterase; Alzheimer Disease; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Mice; Passiflora; Plant Extracts; Seeds; Stilbenes

Alzheimer's disease (AD), also known as senile dementia, is the most common degenerative disease of the central nervous system. Neuroinflammation is currently believed to be a crucial factor in the progression of AD, while its exact mechanism remains unclear. In this study, we demonstrated that AD transgenic mice exhibited cognitive deficits accompanied by the elevated serum and brain inflammation. Treating with a natural active ingredient tetrahydroxy stilbene glucoside (TSG) from the Chinese herb Polygonum multiflorum that has been well known for its unique anti-aging effect, learning-memory ability of AD mice was distinctly improved. Meanwhile, it was observed that the expressions of serum inflammatory cytokines and the activation of microglia in cerebral cortex and hippocampus were suppressed after TSG treatment, which was probably attributable to the decrease of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) triggered immune response and NLRP3 inflammasome activation. Furthermore, cell culture experiments employing LPS combined with IFN-γ induced microglia activation showed that TSG reversed the polarization status of M1-type microglia to restore the quiescence, and cGAS-STING elevation was observed in the activated microglia and normalized by TSG incubation. In addition, TSG suppressed the production of inflammatory cytokines such as IL-1β, IL-6, TNF-α, IFN-α and IFN-β, as well as the expression of IFN regulatory proteins such as IFIT1 and IRF7 in the LPS/IFN-γ-stimulated inflammatory response in BV2 cell. Finally, it was also verified that TSG are, in part, through a cGAS-STING dependent pathway and triggered NLRP3 inflammasome activation to inhibit neuroinflammation through interfering with cGAS-STING inhibitors. Taken together, our findings highlight the health benefits of TSG and its potential application in preventing cognitive disorders by inhibiting neuroinflammation through cGAS-STING signaling pathway in AD.

Topics: Alzheimer Disease; Animals; Cytokines; Glycosides; Inflammasomes; Lipopolysaccharides; Mice; Mice, Transgenic; Neuroinflammatory Diseases; NLR Family, Pyrin Domain-Containing 3 Protein; Nucleotidyltransferases; Stilbenes

Mitochondrial dysfunction leading to overproduction of oxygen free radicals is an important event in the development of Alzheimer's disease. Tetrahydroxy stilbene glycoside (TSG) is one of the main effective components of Polygonum multiflorum and has a certain free radical scavenging effect. We synthesized tetrahydroxy stilbene glycoside derivatives (Mito-TSGs) that can cross the mitochondrial membrane and may provide effective protection against Alzheimer's disease. This experiment investigates the protective mechanism of tetrahydroxy stilbene glycoside derivatives against mitochondrial free radical damage and apoptosis in APP695V717I transgenic model mice. The experimental subjects were healthy 3-month-old APP695V717I transgenic model mice, while C57BL/6J mice of the same age and genetic background served as controls. The results demonstrated that the tetrahydroxy stilbene glycoside derivatives significantly improved mouse behavioral performance. It also led to a decrease in the levels of H2O2, NO, MDA, and LD, along with an increase in LDH activity and in the antioxidant enzyme activity of SOD, CAT, and GSH-Px. Moreover, it elevated the mitochondrial membrane potential, decreased the gene and protein expression of Caspase-3 and Bax, and increased the gene and protein expression of Bcl-2. Notably, the effectiveness of tetrahydroxy stilbene glycoside derivatives was superior to that of traditional tetrahydroxy stilbene glycoside.

Topics: Alzheimer Disease; Animals; Antioxidants; Apoptosis; Free Radicals; Glycosides; Hydrogen Peroxide; Mice; Mice, Inbred C57BL; Mice, Transgenic; Stilbenes

Dual-phase amyloid PET is considered a useful protocol to study patients with cognitive impairment. Early-phase 18F-florbetaben PET/CT has been proposed as a surrogate of 18F-FDG PET/CT providing information related to regional brain perfusion. We report the case of a 61-year-old woman referred to the cognitive impairment unit for study, preliminary diagnosed as probable Alzheimer disease. The dual-phase 18F-florbetaben PET/CT was shown as the main finding, no uptake in the left anterior thalamus. Memory and language symptoms have been described as primary clinical features of anterior thalamic infarctions that could be confused with the main manifestations of Alzheimer disease.

Topics: Alzheimer Disease; Aniline Compounds; Cerebral Infarction; Female; Humans; Middle Aged; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Stilbenes

Alzheimer's disease (AD) is a neurodegenerative disease in elderly population. Pterostilbene (PTS) is a resveratrol analog with neuroprotective activity. However, the biological mechanisms of PTS in AD progression are largely uncertain. An animal model of AD was established using streptozotocin (STZ)-treated C57BL/6J mice. Monoamine oxidase B (MAOB) expression was analyzed by bioinformatics analysis and detected by western blotting assay. The memory impairment was investigated by Morris water maze test. The levels of Tau hyperphosphorylation and death-related proteins were detected by western blotting analysis. The levels of amyloid β (Aβ)

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; bcl-2-Associated X Protein; Caspase 3; Disease Models, Animal; Humans; Inflammation; Interleukin-6; Mice; Mice, Inbred C57BL; Monoamine Oxidase; Neurodegenerative Diseases; NF-kappa B; Reactive Oxygen Species; Resveratrol; Stilbenes; Streptozocin; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Neurodegenerative diseases such as Alzheimer's disease (AD) are associated with progressive neuronal cell death, and they are commonly correlated with aberrant protein misfolding and aggregation of Aβ peptides. Transition metal ions (Cu, Fe, and Zn) have been shown to promote aggregation and oxidative stress through formation of Aβ-metal complexes. In this context, integrating molecular scaffolds rationally is used here to generate multifunctional molecules as modulators for metal-induced abnormalities. This work encompasses two azo-stilbene (

Topics: Acetylcholinesterase; Alzheimer Disease; Amines; Amyloid beta-Peptides; Chelating Agents; Copper; Humans; Metals; Molecular Docking Simulation; Pyridines; Stilbenes

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease that is the most common cause of dementia in the elderly. Aβ1‑42 is significantly associated with memory deficits and it can increase the level of acetylcholine, promote the activity of acetylcholinesterase (AChE), and cause cognitive dysfunction. Isorhapontigenin (ISO) is a stilbene derivative that has antioxidant, anti‑tumor, and anti‑inflammatory effects. However, it is still unclear whether ISO can affect β‑amyloid‑associated cognitive impairments. In this study, we found that ISO improved cognitive dysfunction induced by Aβ1‑42 in rats. It inhibited the Aβ‑induced activation of M1 microglia and reduced the release of inflammatory cytokines. It alleviated amyloid beta‑induced oxidative stress and led to an overall improvement in AD symptoms. Cellularly, we found that ISO alleviated Aβ‑induced inflammation and oxidative stress by activating the PI3K/AKT/GSK‑3β pathway and ultimately improved cognitive dysfunction in AD rats.

Topics: Acetylcholine; Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Antioxidants; Cognitive Dysfunction; Cytokines; Disease Models, Animal; Glycogen Synthase Kinase 3 beta; Neurodegenerative Diseases; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; Stilbenes

To assess the correlation between profile and severity deterioration in the neuropsychological assessment and the most affected regions in amyloid PET semiquantification. The influence of vascular risk and other potential confounding factors was also evaluated.. A retrospective, observational, and multicenter study including all patients referred for amyloid PET in daily practice was conducted. Patients underwent neuropsychological assessment, and cognitive decline severity and domain(s) affected were recorded. The patients were grouped according to cognitive impairment (CI) profile and severity: (A) no CI, single-domain amnestic CI, multiple-domain amnestic CI, and nonamnestic CI; and (B) mild CI, moderate and severe dementia. An adapted Framingham Stroke Risk Profile was calculated for each individual. Depression and parkinsonism were also recorded. Standardized quantitative analysis software was used to obtain standardized uptake value ratio (SUVR) values from PET/CT images. The corresponding associations were assessed with the most appropriate statistical tests.. One hundred twenty-nine patients were included (62 men, 67 women; 64.67 ± 7.47 years old). Significant differences in global and regional amyloid load were exclusively found in women between non-CI and moderate dementia ( P = 0.006, for total-cerebellum SUVR). Posterior and anterior cingulates and prefrontal cortex best represented CI severity ( P = 0.003, 0.006, and 0.006, respectively). No relationship between the CI profile and the regional amyloid load was shown. A significantly high positive correlation was found between age and vascular risk and between these variables and amyloid load in nearly all regions, especially in women with moderate dementia.. Semiquantitative analysis of amyloid PET by SUVR values revealed a significant correlation between amyloid burden and CI severity, although only in women.

Topics: Aged; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloidosis; Aniline Compounds; Brain; Cognitive Dysfunction; Dementia; Female; Humans; Male; Middle Aged; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Retrospective Studies; Stilbenes

Alzheimer's disease (AD) is a serious, progressive neurodegenerative disease that involves irreversible neuronal death. Tetrahydroxy stilbene glycoside (TSG) is an active compound extracted from P. multiflorum, a traditional Chinese herbal medicine, but its role in neuroprotection is unclear. Herein, we aimed to validate the effects of TSG on APP/PS1 model mice and the underlying mechanism. RNA-seq was performed to identify differentially expressed genes in APP/PS1 mouse, with PCR and immunohistochemistry used for validation. Experiments were performed after bioinformatic analysis for verification. Neuronal damage was observed by H&E staining. Key proteins involved in the pathway such as CX3CR1, Iba1 and TGF-β were examined by immunohistochemical analysis. The KEGG analysis suggested that these genes might act by multiple pathways to build the pharmacological network of TSG in AD progression. These data provide the credible evidence that TSG improved neuronal damage and regulated neuroprotective mechanisms. Together, our work has detailed the whole and major genes in APP/PS1 model mouse regulated by TSG, and highlighted the anti-inflammatory function of TSG in mediating CX3CR1 and TGF-β as the TGF-β/fractalkine/CX3XR1 signaling pathway, especially in microglia. Moreover, TSG has potential value in synaptic transmission and neurotrophic action on neurodegenerative diseases. In summary, TSG is a promising candidate for preventing and treating the progression of AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemokine CX3CL1; Computational Biology; CX3C Chemokine Receptor 1; Disease Progression; Gene Expression Regulation; Humans; Immunohistochemistry; Mice; Mice, Transgenic; Neuroprotective Agents; Oligopeptides; RNA-Seq; Signal Transduction; Stilbenes; Transforming Growth Factor beta

Global and regional changes in cerebral blood flow (CBF) can result in biased quantitative estimates of amyloid load by PET imaging. Therefore, the current simulation study assessed effects of these changes on amyloid quantification using a reference tissue approach for [

Topics: Alzheimer Disease; Aniline Compounds; Benzothiazoles; Case-Control Studies; Cerebrovascular Circulation; Fluorine Radioisotopes; Humans; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes

Amyloid PET which has been widely used for noninvasive assessment of cortical amyloid burden is visually interpreted in the clinical setting. As a fast and easy-to-use visual interpretation support system, we analyze whether the deep learning-based end-to-end estimation of amyloid burden improves inter-reader agreement as well as the confidence of the visual reading.. A total of 121 clinical routines [. Inter-reader agreements for the visual reading based on a 3-point scale (BAPL score) calculated by Fleiss kappa coefficients were 0.46 and 0.76 for the visual reading without and with the deep learning system, respectively. For the two reading sessions, the confidence score of visual reading was improved at the visual reading session with the output (1.27 ± 0.078 for visual reading-only session vs. 1.66 ± 0.63 for a visual reading session with the deep learning system).. Our results highlight the impact of deep learning-based one-step amyloid burden estimation system on inter-reader agreement and confidence of reading when applied to clinical routine amyloid PET reading.

Topics: Alzheimer Disease; Amyloid; Aniline Compounds; Deep Learning; Humans; Positron-Emission Tomography; Stilbenes

Metabolic syndrome (MetS) is associated with dementia, but it is unclear whether MetS is related to Alzheimer's disease (AD). We investigated the association of MetS with brain amyloid, a key AD feature, and neurodegeneration. A community-based sample of 350 middle-aged Hispanics in New York City had cerebral amyloid β (Aβ) burden ascertained with

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Blood Glucose; Brain; Diffusion Tensor Imaging; Female; Hispanic or Latino; Humans; Male; Metabolic Syndrome; Middle Aged; Nerve Degeneration; New York; Risk; Stilbenes; Triglycerides

In the present study, effect of pterostilbene on β-amyloid 1-42 (Aβ. The behavior results show that pterostilbene alleviated Aβ. The present study reports that pterostilbene alleviated Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Brain; Cell Line; Cognitive Dysfunction; Disease Models, Animal; Humans; Male; Memory, Short-Term; Mice; Neurons; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Peptide Fragments; Signal Transduction; Stilbenes

This longitudinal study evaluates the prognostic impact of amyloid PET in patients suspected of Alzheimer's disease and presenting with isolated cerebrospinal fluid (CSF) increases in P-Tau proteins (NCT02556502). The rate of conversion, based on the DSM-5 criteria and all collected data (average follow-up of 39.2±13.2 months), was determined by a panel of experts blinded to the PET results and was 75%(6/8) for positive and 35%(6/17) for negative baseline amyloid PET. In this population with isolated CSF increases in P-Tau, a positive baseline amyloid PET was associated with greater than twice the proportion of dementia conversions within the following three years.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloidogenic Proteins; Aniline Compounds; Biomarkers; Female; Fluorine Radioisotopes; France; Humans; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Positron-Emission Tomography; Prognosis; Stilbenes; tau Proteins

To date, 3

Topics: Aged; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Humans; Stilbenes

Emerging evidence indicates a central role of gliosis in Alzheimer's disease (AD) pathophysiology. However, the regional distribution and interaction of astrogliosis and microgliosis in association with amyloid-β (Aβ) still remain uncertain.. Here we studied the pathological profiles in autopsy AD brain by using specific imaging tracers.. Autopsy brain tissues of AD (n = 15, age 70.4±8.5 years) and control cases (n = 12, age 76.6±10.9) were examined with homogenate binding assays, autoradiography for Aβ plaques (3H-florbetaben/3H-PIB), astrogliosis (3H-L-deprenyl), and microgliosis (3H-PK11195/3H-FEMPA), as well as immunoassays.. In vitro saturation analysis revealed high-affinity binding sites of 3H-florbetaben, 3H-L-deprenyl, and 3H-PK11195/3H-FEMPA in the frontal cortex of AD cases. In vitro3H-florbetaben binding increased across cortical and subcortical regions of AD compared to control with the highest binding in the frontal and parietal cortices. The in vitro3H-L-deprenyl binding showed highest binding in the hippocampus (dentate gyrus) followed by cortical and subcortical regions of AD while the GFAP expression was upregulated only in the hippocampus compared to control. The in vitro3H-PK11195 binding was solely increased in the parietal cortex and the hippocampus of AD compared to control. The 3H-florbetaben binding positively correlated with the 3H-L-deprenyl binding in the hippocampus and parietal cortex of AD and controls. Similarly, a positive correlation was observed between 3H-florbetaben binding and GFAP expression in hippocampus of AD and control.. The use of multi-imaging tracers revealed different regional pattern of changes in autopsy AD brain with respect to amyloid plaque pathology versus astrogliosis and microgliosis.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Autopsy; Brain; Case-Control Studies; Female; Gliosis; Humans; Isoquinolines; Male; Middle Aged; Neuroglia; Plaque, Amyloid; Positron-Emission Tomography; Selegiline; Stilbenes

A low amount and extent of Aβ deposition at early stages of Alzheimer's disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using. The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition ("gray zone"), and subjects with established Aβ pathology.. SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the "gray zone" or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology.. This study supports the utility of using two cutoffs for amyloid PET abnormality defining a "gray zone": a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention.. Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov ( NCT00928304 , NCT00750282 , NCT01138111 , NCT02854033 ) and EudraCT (2014-000798-38).

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Humans; Positron-Emission Tomography; Stilbenes

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Biomarkers; Butyrylcholinesterase; Carbon Radioisotopes; Cholinesterase Inhibitors; Disease Models, Animal; Disease Progression; Female; Fluorine Radioisotopes; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Structure; Nerve Tissue Proteins; Neuroimaging; Plaque, Amyloid; Positron Emission Tomography Computed Tomography; Radiopharmaceuticals; Stilbenes; Tissue Distribution

Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aβ)-positive EOAD, 200 Aβ-negative EOnonAD that meet National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [

Topics: Alzheimer Disease; Aniline Compounds; Autopsy; Biomarkers; Brain; Cognitive Dysfunction; Early Diagnosis; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; National Institute on Aging (U.S.); Positron-Emission Tomography; Stilbenes; United States

Alzheimer's disease perpetually demands enormous research on the development of effective treatment strategies. The present study aims to define the role of Oxyresveratrol (OXY) alone and in combination with Alkoxy glycerols (AKG) to reduce Tau protein level and improve the climbing behaviour of Drosophila fly models expressed with human-Tau protein. Oxyresveratrol, a polyphenolic stilbene, possesses a wide range of biological activities like antioxidant, anti-inflammatory, and neuroprotective effects. Nevertheless, chemical instability and low solubility of OXY in aqueous solutions reduce its bioavailability and hinder it from exerting neuroprotective activities. An inclusion complex of OXY with β- cyclodextrin (CD) (OXY-CD complex) was employed in the study for increased dissolution rate and oral availability of OXY. Fish oils and their derivatives have a plethora of applications in in vivo biological activities. Herein, we also remark on the role of AKG in reducing Tau protein level in flies by enhancing OXY-CD activity. Dietary supplementation of OXY-CD together with AKG improved the learning and memory abilities during the climbing assay in Tau flies. The study highlights OXY-CD and AKG as neuroprotective agents and put forward a plausible approach towards the increased permeability of pharmacological agents across the blood-brain barrier (BBB) for the central nervous system elicited by AKG.

Topics: Alzheimer Disease; Animals; Animals, Genetically Modified; Behavior, Animal; Benzofurans; Drosophila melanogaster; Glycerol; Humans; Learning; Memory; Neuroprotective Agents; Plant Extracts; Stilbenes; tau Proteins

Amyloid beta peptide (Aβ) has been confirmed to be an essential reason of Alzheimer's disease (AD) for a long time. Ferroptosis is a newly recognized oxidative cell death mechanism, which is highly related to AD. Recently, tetrahydroxy stilbene glycoside (TSG) has been beneficial in alleviating learning and memory of AD and aged mouse model. Unfortunately, the underlying mechanisms between TSG and ferroptosis in AD are poorly understood. Herein, we investigated whether neural cells in cerebral cortex and hippocampus that were seriously afflicted in APP/PS1 mice might be vulnerable to ferroptosis. Treatment with non-toxic TSG dose-dependently resisted Aβ-caused cytotoxic death in neuronal cells by regulating ferroptosis related proteins and enzymes in APP/PS1 mice. TSG also alleviated cellular oxidative stress and inflammatory damage in response to Aβ by attenuating the levels of oxidation products. Importantly, TSG administration abrogated Aβ-caused brain damage, indicating that TSG rescued brain cells. Subsequently, TSG promoted the activation of GSH/GPX4/ROS and Keap1/Nrf2/ARE signaling pathways. Notably, markers related to ferroptosis including increased lipid peroxidation, enhanced neuroinflammation such as NLRP3, and also the expression of DMT1, ACSL4 and NCOA4, were reduced by TSG administration. In addition, TSG enhanced antioxidative stress via the upregulation of SOD, and the expression of FTH1, CD98 and xCT. Taken together, our data indicated a novel mechanism of TSG in reversing Aβ-caused injury through restoring mitochondrial function via several signaling pathways, implying a promising candidate against neurodegenerative diseases especially AD. Hence, TSG should be taken into consideration during treatment of AD in the future.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Ferroptosis; Glutathione Peroxidase; Glycosides; Hippocampus; Kelch-Like ECH-Associated Protein 1; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-E2-Related Factor 2; Presenilin-1; Reactive Oxygen Species; Stilbenes

This study investigated changes in brain perfusion and Aβ burden according to the progression of Alzheimer's disease (AD) by using a dual-phase. Sixty subjects, including 12 with Aβ-negative normal cognition (Aβ. Both the R1 and eFBB perfusion reductions in the cortical regions were not significantly different between the Aβ. The results of this study demonstrated the feasibility of dual-phase

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cerebrovascular Circulation; Humans; Perfusion; Positron-Emission Tomography; Stilbenes

The purpose of this study is to provide a complete metabolic profile of the hydroalcoholic extracts of the leaves and fruits of

Topics: Acetylcholine; Alzheimer Disease; Animals; Arecaceae; Brain; Cholinesterase Inhibitors; Disease Models, Animal; Fatty Acids; Flavonoids; Fruit; Lignans; Plant Extracts; Plant Leaves; Rats; Stilbenes

Drugs promoting myelin repair represent a promising therapeutic approach in multiple sclerosis and several candidate molecules are currently being evaluated, fostering the need of a quantitative method to specifically measure myelin content in vivo. PET using the benzothiazole derivative. Four baboons underwent a 90-min dynamic PET scan for each radioligand. Arterial blood samples were collected during the exam for each radiotracer, except for. In WM,. Given their higher binding and longer half-life, our study indicates that

Topics: Alzheimer Disease; Aniline Compounds; Animals; Benzothiazoles; Brain; Carbon Radioisotopes; Drug Repositioning; Ethylene Glycols; Humans; Myelin Sheath; Positron-Emission Tomography; Stilbenes

Vascular dysfunction is correlated to the incidence and severity of Alzheimer's disease. In a mouse model of Alzheimer's disease (APP/PS1) using in vivo, time-lapse, multiphoton microscopy, we found that occlusions of the microvasculature alter amyloid-beta (Aβ) plaques. We used several models of vascular injury that varied in severity. Femtosecond laser-induced occlusions in single capillaries generated a transient increase in small, cell-sized, Aβ deposits visualized with methoxy-X04, a label of fibrillar Aβ. After occlusions of penetrating arterioles, some plaques changed morphology, while others disappeared, and some new plaques appeared within a week after the lesion. Antibody labeling of Aβ revealed a transient increase in non-fibrillar Aβ one day after the occlusion that coincided with the disappearance of methoxy-X04-labeled plaques. Four days after the lesion, anti-Aβ labeling decreased and only remained in patches unlabeled by methoxy-X04 near microglia. Histology in two additional models, sparse embolic occlusions from intracarotid injections of beads and infarction from photothrombosis, demonstrated increased labeling intensity in plaques after injury. These results suggest that microvascular lesions can alter the deposition and clearance of Aβ and confirm that Aβ plaques are dynamic structures, complicating the interpretation of plaque burden as a marker of Alzheimer's disease progression.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Arterioles; Female; Immunohistochemistry; Intracranial Thrombosis; Male; Mice; Mice, Transgenic; Microglia; Microscopy, Fluorescence, Multiphoton; Microvessels; Plaque, Amyloid; Stilbenes; Stroke

We developed a new method to directly calculate Centiloid (CL) units of. Paired FBB and FMM PET scans were obtained from 20 Alzheimer's disease-related cognitive impairment patients, 16 old controls, and 20 young controls. We investigated the correlations between the FBB and FMM CL units using the direct comparison of FBB-FMM CL (dcCL) method and the standard CL method and compare differences in FBB and FMM CL units between dcCL method and the standard method.. Following the conversion of FBB or FMM SUVRs into CL units, a direct relationship was formed between the FBB or FMM SUVRs and the CL units using dcCL method (FBB dcCL = 151.42 × FBB dcSUVR - 142.24 and FMM dcCL = 148.52 × FMM dcSUVR - 137.09). The FBB and FMM CL units were highly correlated in both our method (R. Our findings suggest that our direct comparison of FBB-FMM method, rather than the standard method, is a reasonable way to convert FBB or FMM SUVRs into CL units, at least in environments where FBB or FMM ligands are used frequently.

Topics: Alzheimer Disease; Aniline Compounds; Benzothiazoles; Brain; Humans; Positron-Emission Tomography; Stilbenes

We developed a machine learning-based classifier for in vivo amyloid positron emission tomography (PET) staging, quantified cortical uptake of the PET tracer by using a machine learning method, and investigated the impact of these amyloid PET parameters on clinical and structural outcomes.. A total of 337. The classification accuracy was 97.3% for cortical amyloid positivity and 91.1% for striatal positivity. The left frontal and precuneus/posterior cingulate regions, as well as the anterior portion of the striatum, were important in determination of stages. The clinical scores and magnetic resonance imaging parameters showed negative associations with PET stage. However, except for the hippocampal volume, most outcomes were associated with the stage through the complete mediation effect of pRCTU.. Using a machine learning algorithm, we achieved high accuracy for in vivo amyloid PET staging. The in vivo amyloid stage was associated with cognitive function and cerebral atrophy mostly through the mediation effect of cortical amyloid.

Topics: Alzheimer Disease; Aniline Compounds; Brain; Cognitive Dysfunction; Humans; Machine Learning; Positron-Emission Tomography; Stilbenes

Digital brain template and atlas designed for a specific group provide advantages for the analysis and interpretation of neuroimaging data, but require a significant workload for development. We developed a simple method to create customized brain atlas for diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL) tool using FreeSurfer-generated volume-of-interest (FSVOI) images and validated.. Customized FreeSurfer-based brain atlas for DARTEL tool is easy to create and useful for the analysis of PET and MR images with high adaptability and reliability for broad research purposes.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Biomarkers; Brain; Cross-Sectional Studies; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multimodal Imaging; Phantoms, Imaging; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Stilbenes

Two tridentate ligand systems bearing N-heterocyclic carbene (NHC), amine and carboxylate donor groups coupled to benzothiazole- or stilbene-based amyloid binding moieties were synthesised. Reaction of the imidazolium salt containing pro-ligands with Re(CO)5Cl yielded the corresponding rhenium metal complexes which were characterised by NMR, and X-ray crystallography. These ligands are of interest for the potential preparation of technetium-99m imaging agents for Alzheimer's disease and the capacity of these rhenium complexes bind to amyloid fibrils composed of amyloid-β peptide and amyloid plaques in human frontal cortex brain tissue was evaluated using fluorescence microscopy. These studies show that the complexes bound efficiently to amyloid-β fibrils and some evidence of binding to amyloid-β plaques.

Topics: Alzheimer Disease; Amines; Amyloid beta-Peptides; Benzothiazoles; Binding Sites; Carboxylic Acids; Coordination Complexes; Humans; Ligands; Molecular Structure; Organotechnetium Compounds; Prefrontal Cortex; Rhenium; Stilbenes

The lack of effective Alzheimer's disease treatment is becoming a challenge for researchers and prompts numerous attempts to search for and develop better therapeutic solutions. Compounds that affect several routes of the neurodegeneration cascade leading to the development of disease are of particular interest. An example of such substances is resveratrol and its synthetic and natural derivatives, which have gained popularity in recent years and show promise as a possible new therapeutic option in the approach to Alzheimer's disease treatment. In this article, the state of the art evidence on the role of resveratrol (RSV) in neuroprotection is presented; research results are summarized and the importance of resveratrol and its derivatives in the treatment of Alzheimer's disease are underlined. It also focuses on various modifications of the resveratrol molecule that should be taken into account in the design of future research on drugs against Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzofurans; Blood-Brain Barrier; Central Nervous System Diseases; Humans; Inflammation; Metabolic Diseases; Neuroprotection; Oxidative Stress; Resveratrol; Stilbenes; tau Proteins

Topics: Alzheimer Disease; AMP-Activated Protein Kinases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Cognitive Dysfunction; Disease Models, Animal; Gene Expression Regulation; Glucosides; Humans; Inflammasomes; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Mitochondria; Mitophagy; Neurons; Neuroprotective Agents; NLR Family, Pyrin Domain-Containing 3 Protein; Primary Cell Culture; Protein Kinases; RNA, Small Interfering; Signal Transduction; Stilbenes; Ubiquitin-Protein Ligases

18F-florbetaben (FBB) and 18F-flutemetamol (FMM) amyloid PET have been developed and approved for clinical use. It is important to understand the distinct features of these ligands to compare and correctly interpret the results of different amyloid PET studies.. We performed a head-to-head comparison of FBB and FMM to compare with regard to imaging characteristics, including dynamic range of retention, and differences in quantitative measurements between the two ligands in cortical, striatal, and white matter (WM) regions.. Paired FBB and FMM PET images were acquired in 107 participants. Correlations of FBB and FMM amyloid deposition in the cortex, striatum, and WM were investigated and compared in different reference regions (cerebellar gray matter (CG), whole cerebellum (WC), WC with brainstem (WC + B), and pons).. The cortical SUVR (R2 = 0.97) and striatal SUVR (R2 = 0.95) demonstrated an excellent linear correlation between FBB and FMM using a WC as reference region. There was no difference in the cortical SUVR ratio between the two ligands (p = 0.90), but the striatal SUVR ratio was higher in FMM than in FBB (p < 0.001). Also, the effect size of differences in striatal SUVR seemed to be higher with FMM (2.61) than with FBB (2.34). These trends were similarly observed according to four different reference regions (CG, WC, WC + B, and pons).. Our findings suggest that FMM might be better than FBB to detect amyloid burden in the striatum, although both ligands are comparable for imaging AD pathology in vivo.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Cerebral Cortex; Cognitive Dysfunction; Corpus Striatum; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Positron-Emission Tomography; Stilbenes

Molecules capable of engaging with multiple targets associated with pathological condition of Alzheimer's disease have proved to be potential anti-Alzheimer's agents. In our goal to develop multitarget-directed ligands for the treatment of Alzheimer's disease, a novel series of carbazole-based stilbene derivatives were designed by the fusion of carbazole ring with stilbene scaffold. The designed compounds were synthesized and evaluated for their anti-AD activities including cholinesterase inhibition, Aβ aggregation inhibition, antioxidant and metal chelation properties. Amongst them, (E)-1-(4-(2-(9-ethyl-9H-carbazol-3-yl)vinyl)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)thiourea (50) appeared to be the best candidate with good inhibitory activities against AChE (IC

Topics: Alzheimer Disease; Humans; Molecular Docking Simulation; Molecular Structure; Stilbenes; Structure-Activity Relationship

A series of furocoumarin-stilbene hybrids has been synthesized and evaluated in vitro for inhibitory effect against acetylcholinesterase (AChE), butyrylcholinestarase (BChE), β-secretase, cyclooxygenase-2 (COX-2), and lipoxygenase-5 (LOX-5) activities including free radical-scavenging properties. Among these hybrids, 8-(3,5-dimethoxyphenyl)-4-(3,5-dimethoxystyryl)furochromen-2-one 4h exhibited significant anticholinesterase activity and inhibitory effect against β-secretase, COX-2 and LOX-5 activities. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and an in vitro cell-based antioxidant activity assay involving lipopolysaccharide induced reactive oxygen species production revealed that 4h has capability of scavenging free radicals. Molecular docking into AChE, BChE, β-secretase, COX-2 and LOX-5 active sites has also been performed.

Topics: Alzheimer Disease; Antioxidants; Cell-Free System; Cholinesterase Inhibitors; Cyclooxygenase 2 Inhibitors; Furocoumarins; HEK293 Cells; Humans; Lipoxygenase Inhibitors; MCF-7 Cells; Molecular Docking Simulation; Nootropic Agents; Reactive Oxygen Species; Stilbenes; Structure-Activity Relationship

Odor identification ability may serve as an important diagnostic biomarker in Alzheimer's disease (AD). The aim of the study is to investigate the contribution of A/T/N neuroimaging biomarkers to impaired odor identification ability in the Alzheimer's disease spectrum. In 127 participants, we compared A/T/N neuroimaging biomarkers between normosmia and hyposmia groups, and performed correlation analysis between the biomarkers and Cross-Cultural Smell Identification Test (CCSIT) scores. Additionally, path analysis for odor identification ability was performed using cognitive function as a mediator. In between-group comparison, individuals with hyposmia showed higher frequency of amyloid-β (Aβ) positivity, and lower neuropsychological test performance than those with normosmia. After correction for covariates including total cognition scores, there was no difference in the Aβ or tau burden between the normosmia and hyposmia groups, and no correlation between CCSIT scores and Aβ or tau burden. Meanwhile, cortical volumes in the lateral and medial temporal cortices were smaller in the hyposmia group and decreased with the worsening of CCSIT scores. Path analysis showed that only neurodegeneration had a direct effect on odor identification, while Aβ and tau burden contributed to odor identification with the mediation of cognition. In the Alzheimer's disease spectrum, impaired odor identification ability may be attributable to neurodegeneration rather than the direct effect of Aβ or tau burden.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Anosmia; Biomarkers; Brain; Brain Mapping; Carbolines; Female; Fluorine Radioisotopes; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Odorants; Olfaction Disorders; Positron Emission Tomography Computed Tomography; Smell; Stilbenes; tau Proteins

The degree of alpha attenuation from eyes-closed (EC) to eyes-open (EO) has been suggested as a neural marker of cognitive health, and its disruption has been reported in patients with clinically defined Alzheimer's disease (AD) dementia.. We tested if EC-to-EO alpha reactivity was related to cerebral amyloid-β (Aβ) deposition during the early stage of AD.. Non-demented participants aged ≥55 years who visited the memory clinic between March 2018 and June 2019 (N = 143; 67.8% female; mean age±standard deviation, 74.0±7.6 years) were included in the analyses. Based on the [18F]florbetaben positron emission tomography assessment, the participants were divided into Aβ+ (N = 70) and Aβ- (N = 73) groups. EEG was recorded during the 7 min EC condition followed by a 3 min EO phase, and a Fourier transform spectral analysis was performed.. A significant three-way interaction was detected among Aβ positivity, eye condition, and the laterality factor on alpha-band power after adjusting for age, sex, educational years, global cognition, depression, medication use, and white matter hyperintensities on magnetic resonance imaging (F = 5.987, p = 0.016); EC-to-EO alpha reactivity in the left hemisphere was significantly reduced in Aβ+ subjects without dementia compared with the others (F = 3.984, p = 0.048).. Among mild cognitive impairment subjects, alpha reactivity additively contributed to predict cerebral Aβ positivity beyond the clinical predictors, including vascular risks, impaired memory function, and apolipoprotein E ɛ4. These findings support that EC-to-EO alpha reactivity acts as an early biomarker of cerebral Aβ deposition and is a useful measurement for screening early-stage AD.

Topics: Aged; Aged, 80 and over; Alpha Rhythm; Alzheimer Disease; Aniline Compounds; Electroencephalography; Eye; Female; Fluorine Radioisotopes; Humans; Male; Ocular Physiological Phenomena; Positron-Emission Tomography; Stilbenes

We aimed to quantitatively and qualitatively assess whether there is a discrepancy in detecting amyloid beta (Aβ) positivity between 18F-florbetaben (FBB) and 18F-flutemetamol (FMM) positron emission tomography (PET). We obtained paired FBB and FMM PET images from 107 participants. Three experts visually quantified the Aβ deposition as positive or negative. Quantitative assessment was performed using global cortical standardized uptake value ratio (SUVR) with the whole cerebellum as the reference region. Inter-rater agreement was excellent for FBB and FMM. The concordance rates between FBB and FMM were 94.4% (101/107) for visual assessment and 98.1% (105/107) for SUVR cut-off categorization. Both FBB and FMM showed high agreement rates between visual assessment and SUVR positive or negative categorization (93.5% in FBB and 91.2% in FMM). When the two ligands were compared based on SUVR cut-off categorization as standard of truth, although not statistically significant, the false-positive rate was higher in FMM (9.1%) than in FBB (1.8%) (p = 0.13). Our findings suggested that both FBB and FMM had excellent agreement when used to quantitatively and qualitatively evaluate Aβ deposits, thus, combining amyloid PET data associated with the use of different ligands from multi-centers is feasible.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Case-Control Studies; Cognitive Dysfunction; Dementia, Vascular; False Negative Reactions; False Positive Reactions; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes

Amyloid PET allows for the assessment of amyloid β status in the brain, distinguishing true Alzheimer's disease from Alzheimer's disease-mimicking conditions. Around 15-20% of patients with clinically probable Alzheimer's disease have been found to have no significant Alzheimer's pathology on amyloid PET. However, a limited number of studies had been conducted on this subpopulation in terms of clinical progression.. We investigated the risk factors that could affect the progression to dementia in patients with amyloid-negative amnestic mild cognitive impairment (MCI).. This study was a single-institutional, retrospective cohort study of patients over the age of 50 with amyloid-negative amnestic MCI who visited the memory clinic of Asan Medical Center with a follow-up period of more than 36 months. All participants underwent brain magnetic resonance imaging (MRI), detailed neuropsychological testing, and fluorine-18[F18]-florbetaben amyloid PET.. During the follow-up period, 39 of 107 patients progressed to dementia from amnestic MCI. In comparison with the stationary group, the progressed group had a more severe impairment in verbal and visual episodic memory function and hippocampal atrophy, which showed an Alzheimer's diseaselike pattern despite the lack of evidence for significant Alzheimer's disease pathology. Voxel-based morphometric MRI analysis revealed that the progressed group had a reduced gray matter volume in the bilateral cerebellar cortices, right temporal cortex, and bilateral insular cortices.. Considering the lack of evidence of amyloid pathology, clinical progression of these subpopulation may be caused by other neuropathologies such as TDP-43, abnormal tau or alpha synuclein that lead to neurodegeneration independent of amyloid-driven pathway. Further prospective studies incorporating biomarkers of Alzheimer's disease-mimicking dementia are warranted.

Topics: Aged; Alzheimer Disease; Amnesia; Aniline Compounds; Brain; Cognitive Dysfunction; Disease Progression; Female; Fluorine Radioisotopes; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Republic of Korea; Retrospective Studies; Risk Factors; Stilbenes; tau Proteins

We analyzed 252 PET/CT scans, visually assessed by each reader three times, applying independently the three different reading criteria proposed. Each reader evaluated the regional uptake specifying for each cortical region a numeric value of grading of positivity in order to assign a final score. At the end of each reading a level of confidence was determined by assigning a score from 0 (negative) to 4 (positive). After first reading, those cases in which the evaluations by two experienced readers did not match (discordant cases) were independently reevaluated merging all the three different visual interpretation criteria.. Good agreement was observed for visual interpretation among the six readers' confidence-level using independently the three visual reading criteria: ICC=0.83 (0.80-0.86) for. All the criteria proposed are useful to determine the grading of positivity or negativity of amyloid deposition and their merging improves the diagnostic confidence and provides a better agreement.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Benzothiazoles; Brain; Ethylene Glycols; Fluorine Radioisotopes; Humans; Image Interpretation, Computer-Assisted; Middle Aged; Positron Emission Tomography Computed Tomography; Stilbenes

Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Brain; Disease Models, Animal; Female; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Plaque, Amyloid; Positron Emission Tomography Computed Tomography; Presenilin-1; Radiopharmaceuticals; Stilbenes

Alzheimer's disease (AD) pathology precedes the onset of clinical symptoms by several decades. Thus, biomarkers are required to identify prodromal disease stages to allow for the early and effective treatment. The methoxy-X04-derivative BSC4090 is a fluorescent ligand which was designed to target neurofibrillary tangles in AD. BSC4090 staining was previously detected in post-mortem brains and olfactory mucosa derived from AD patients. We tested BSC4090 as a potential diagnostic marker of prodromal and early AD using olfactory mucosa biopsies from 12 individuals with AD, 13 with mild cognitive impairment (MCI), and 10 cognitively normal (CN) controls. Receiver-operating curve analysis revealed areas under the curve of 0.78 for AD versus CN and of 0.86 for MCI due to AD versus MCI of other causes. BSC4090 labeling correlated significantly with cerebrospinal fluid levels of tau protein phosphorylated at T181. Using NMR spectroscopy, we find that BSC4090 binds to fibrillar and pre-fibrillar but not to monomeric tau. Thus, BSC4090 may be an interesting candidate to detect AD at the early disease stages.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Benzylidene Compounds; Biopsy; Case-Control Studies; Cognitive Dysfunction; Female; Fluorescent Dyes; Humans; Magnetic Resonance Spectroscopy; Male; Mental Status and Dementia Tests; Microscopy, Confocal; Microscopy, Electron, Transmission; Middle Aged; Olfactory Mucosa; Prodromal Symptoms; Pyrimidines; Stilbenes

The aim of this study was to identify white matter structural networks of amnestic mild cognitive impairment (aMCI) dichotomized by β amyloid (Aβ) status and compare them using network-based statistics (NBS).. Patients underwent whole-brain diffusion-weighted magnetic resonance imaging, detailed neuropsychological test and [. One hundred sixteen participants (Aβ- cognitively normal [CN], n = 35; Aβ- aMCI, n = 42; Aβ+ aMCI, n = 39) were included. There was no subnetwork showing significant difference between Aβ+ aMCI and Aβ- aMCI. However, by comparing each aMCI group with control group, we found that supplementary motor areas were common hub regions. Intriguingly, Aβ+ aMCI showed reduced connectivity mainly in the medial frontal regions, while Aβ- aMCI showed somewhat uniform disruption when compared to CN.. Structural network analysis using network-based approach in aMCI may shed light on further understanding of white matter disruption in the prodromal stage of Alzheimer's disease.

Topics: Aged; Alzheimer Disease; Amnesia; Amyloid; Aniline Compounds; Brain; Brain Mapping; Cerebral Cortex; Cognitive Dysfunction; Diffusion Tensor Imaging; Female; Humans; Male; Neuropsychological Tests; Positron-Emission Tomography; Stilbenes; White Matter

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Brain Diseases; Cognitive Dysfunction; Deep Learning; Female; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Middle Aged; Multimodal Imaging; Parkinsonian Disorders; Positron-Emission Tomography; Retrospective Studies; Stilbenes

Amyloid pathology is a key feature of Alzheimer's disease (AD) and can be assessed in vivo with amyloid positron emission tomography (PET) imaging.. The objective of this study was to evaluate the incremental value of a PET scan with [18F]florbetaben, in terms of changes of diagnosis, diagnostic confidence, and treatment plan when added to a standardized diagnostic workup for cognitive disorders, with particular focus on the role of the neuropsychological assessment, including the Free and Cued Selective Reminding Test (FCSRT).. A total of 104 patients (69 mild cognitive impairment, 35 dementia), with diagnostic uncertainty after diagnostic workup, were recruited from our memory clinic. [18F]florbetaben PET scans were interpreted as amyloid negative or positive on the basis of a semi-quantitative visual rating. Clinical diagnosis and diagnostic confidence for AD or non-AD dementia were rated before and after PET result disclosure, as was the impact of PET on the patient management plan.. There were 69/104 (66%) [18F]florbetaben positive scans, 51/62 (82%) patients were suspected as having AD before the PET scan and 18/42 (43%) were not. Overall, the data obtained at PET changed 18/104 diagnoses (17%) and increased diagnostic confidence from 69.1±8.1% to 83.5±9.1 (p < 0.001), with the greatest impact on diagnosis and confidence in PET negative patients with an initial diagnosis of AD (p < 0.01) and in early-onset patients (p = 0.01).. Amyloid PET represents a source of added value in dementia diagnosis, with a significant effect on diagnosis and diagnostic confidence. However, the use of a complete neuropsychological assessment has an add-on value on limiting the amyloid PET influence on change of diagnosis, and the real impact of amyloid PET should always be weighed up together with an accurate standardized diagnostic workup.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Cognitive Dysfunction; Diagnosis, Differential; Female; Fluorine Radioisotopes; Humans; Male; Neuropsychological Tests; Positron-Emission Tomography; Radioactive Tracers; Reproducibility of Results; Stilbenes

While AD can be definitively confirmed by postmortem histopathologic examination, in vivo imaging may improve the clinician's ability to identify AD at the earliest stage. The aim of the study was to test the performance of amyloid PET using new processing imaging algorithm for more precise diagnosis of AD.. Amyloid PET results using a new processing imaging algorithm (MRI-Less and AAL Atlas) were correlated with clinical, cognitive status, CSF analysis, and other imaging. The regional SUVR using the white matter of cerebellum as reference region and scores from clinical and cognitive tests were used to create ROC curves. Leave-one-out cross-validation was carried out to validate the results.. Forty-four consecutive patients with clinical evidence of dementia, were retrospectively evaluated. Amyloid PET scan was positive in 26/44 patients with dementia. After integration with 18F-FDG PET, clinical data and CSF protein levels, 22 of them were classified as AD, the remaining 4 as vascular or frontotemporal dementia. Amyloid and FDG PET, CDR 1, CSF Tau, and p-tau levels showed the best true positive and true negative rates (amyloid PET: AUC = .85, sensitivity .91, specificity .79). A SUVR value of 1.006 in the inferior frontal cortex and of 1.03 in the precuneus region was the best cutoff SUVR value and showed a good correlation with the diagnosis of AD. Thirteen of 44 amyloid PET positive patients have been enrolled in clinical trials using antiamyloid approaches.. Amyloid PET using SPM-normalized SUVR analysis showed high predictive power for the differential diagnosis of AD.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Positron Emission Tomography Computed Tomography; Retrospective Studies; Sensitivity and Specificity; Stilbenes

As Alzheimer's disease (AD) induces several cellular and molecular damages, it could be interesting to use multi-target molecules for therapeutics. We previously published that trans ε-viniferin induced the disaggregation of Aβ42 peptide and inhibited the inflammatory response in primary cellular model of AD. Here, effects of this stilbenoid were evaluated in transgenic APPswePS1dE9 mice. We report that trans ε-viniferin could go through the blood brain barrier, reduces size and density of amyloid deposits and decreases reactivity of astrocytes and microglia, after a weekly intraperitoneal injection at 10 mg/kg from 3 to 6 months of age.

Topics: Alzheimer Disease; Animals; Astrocytes; Benzofurans; Disease Models, Animal; Female; Inflammation; Male; Mice; Mice, Transgenic; Microglia; Plaque, Amyloid; Stilbenes

Differentiating Alzheimer disease (AD) from other forms of cognitive impairment and from normal aging can be challenging. As a consequence, the diagnosis of AD can be delayed, often occurring too late for meaningful intervention. The role of β-amyloid plaques in the pathogenesis of AD provides a target for highly sensitive and specific image quantification of amyloid plaque burden using β-amyloid PET (F-florbetaben). Here we present the case of a 77-year-old woman with increasing memory impairment and striking white matter changes on MRI, with the "racoon eye" sign on F-florebetaben PET imaging.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Diagnosis, Differential; Female; Humans; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes

Brain amyloid deposition is one of the main hallmarks of Alzheimer's disease (AD) and two approaches are available for assessing amyloid pathology in vivo: cerebrospinal fluid (CSF) biomarkers levels and amyloid load visualized by amyloid beta positron emission tomography imaging (Amy-PET) probes. We aimed to investigate the concordance between CSF biomarkers and Amy-PET in a memory clinic cohort. Moreover, using a proper clinical follow-up, we wanted to assess the diagnostic accuracy of CSF and PET biomarkers in predicting the progression of patients with mild cognitive impairment (MCI) to AD dementia. We included 31 MCI patients who underwent [18F]florbetaben PET and CSF sampling (Aβ1-42, t-Tau, p-Tau). A semiquantitative visual scan assessment was used to quantify amyloid deposition in 5 brain regions, rating from 1 (negative), to 2 and 3 (positive). CSF biomarkers were considered abnormal if: Aβ1-42 < 600 pg/ml, p-Tau/Aβ1-42 > 0.08 and t-Tau/Aβ1-42 > 0.52. We also applied less lenient cutoffs of 550 pg/ml and 450 pg/ml for Aβ1-42. The concordance rate was 77% between Amy-PET and CSF Aβ1-42 levels, and 89% between Amy-PET and p-Tau/Aβ1-42 and t-Tau/Aβ1-42. According to the clinical follow-up, Amy-PET (sensitivity [SE] 93.7%, specificity [SP] 80%) exhibited the best diagnostic accuracy in discriminating AD from non-AD, followed by p-Tau/Aβ1-42 ratio and t-Tau/Aβ1-42 ratio (SE 93.7%, SP 66.6%), and Aβ1-42 levels (SE 81%, SP 60%). The regional uptake of [18F]florbetaben PET in the precuneus and the striatum showed the best SP (86.6%). In discordant cases, the clinical diagnosis was most often in agreement with PET results. In general, concordance between CSF biomarkers and Amy-PET was good, especially when the ratios between CSF amyloid and Tau biomarkers were used. However, Amy-PET proved to be superior to CSF Aβ1-42 in terms of diagnostic accuracy for AD, with the possibility to further increase its specificity by focusing the analysis in specific areas such as the precuneus/posterior cingulate cortex and the striatum.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cerebrospinal Fluid; Cognitive Dysfunction; Disease Progression; Female; Follow-Up Studies; Humans; Male; Middle Aged; Peptide Fragments; Positron-Emission Tomography; Predictive Value of Tests; Sensitivity and Specificity; Stilbenes; tau Proteins

The aim of this study was to assess, in routine, the rates with which an amyloid deposition was documented by 18F-florbetaben PET in patients with suspected Alzheimer's disease (AD) but with isolated increases in cerebrospinal fluid (CSF) tau-protein concentrations, and the subsequent impact of these PET results on medical management.. This prospective study included 34 patients with mild neurocognitive disorders (MND) and suspected AD (73±9 years, 16 women) and with abnormal CSF concentrations in total-tau (T-tau) and/or phosphorylated-tau (P-tau) proteins but normal Aβ42 concentration and Aβ42/Aβ40 ratio. These patients were referred to 8F-florbetaben PET from which the PET-related changes in the confidence for AD diagnosis (low, intermediate, or high) and treatments were reported.. The PET examinations were positive for amyloid deposition (brain amyloid plaque load, BAPL score >1) in none of the 9 patients with an increase in only T-tau proteins and in 8 among the 25 (32%) with an increase in P-tau proteins (one BAPL score of 2 and seven BAPL scores of 3). Knowledge of the PET results was associated with subsequent changes in diagnostic confidence in 44% of patients (15/34) and in the intention-to-treat with a cholinesterase inhibitor drug in 18% (6/34).. In patients with suspected AD and isolated increase in CSF tau protein concentrations, an amyloid deposition is documented by 18F-florbetaben PET in as much as one third of cases when the concentration of P-tau is abnormal, and PET results are associated with significant further changes in medical management.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Amyloidogenic Proteins; Aniline Compounds; Female; Fluorine Radioisotopes; Humans; Male; Neuroimaging; Peptide Fragments; Positron-Emission Tomography; Prospective Studies; Stilbenes; tau Proteins

Data from eighty-eight subjects (52 male subjects, aged 79.8 ± 10.6 years) who underwent antemortem. Against combined Bielschowsky silver staining and immunohistochemistry histopathological scores, statistical parametric mapping had 96% sensitivity, 96% specificity, and 95% accuracy, whereas magnetic resonance-less CapAIBL standardized uptake value ratio. Quantification of

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Autopsy; Brain; Cerebellum; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Sensitivity and Specificity; Stilbenes

Individuals with autosomal dominant Alzheimer's disease (ADAD) present amyloid deposits before symptoms onset. We aimed to investigate efficacy and safety of 18F-florbetaben (FBB) for assessing amyloid deposition in ADAD. We acquired FBB positron emission tomography and magnetic resonance imaging of 25 individuals from PSEN1 families (NCT02362880). We studied individual uptake patterns, group differences, and correlation with estimated years to symptoms onset, as well as adverse events. We found that asymptomatic carriers (N = 14) showed increased FBB uptake across the cerebral cortex and in the caudate. FBB accumulation appeared more than 15 years before onset in the precuneus and bankssts, among other regions, overlapping regions showing increased cortical thickness in the same subjects. FBB uptake correlated with estimated years to symptoms onset in several areas, especially the rostral anterior cingulate. Symptomatic carriers (N = 7) had an elevated FBB uptake plateau. No adverse events were reported. Overall, we found progressive FBB uptake in ADAD starting 2 decades before symptoms. The rostral anterior cingulate is a candidate area to track Aβ deposition in addition to the precuneus.

Topics: Adult; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cerebral Cortex; Female; Fluorine Radioisotopes; Heterozygote; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Positron-Emission Tomography; Presenilins; Radiopharmaceuticals; Stilbenes

Mesenchymal stem cell transplantation is a promising therapeutic approach for Alzheimer's disease (AD). However, poor engraftment and limited survival rates are major obstacles for its clinical application. Resveratrol, an activator of silent information regulator 2, homolog 1 (SIRT1), regulates cell destiny and is beneficial for neurodegenerative disorders. The present study is designed to explore whether resveratrol regulates the fate of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and whether hUC-MSCs combined with resveratrol would be efficacious in the treatment of neurodegeneration in a mouse model of AD through SIRT1 signaling. Herein, we report that resveratrol facilitates hUC-MSCs engraftment in the hippocampus of AD mice and resveratrol enhances the therapeutic effects of hUC-MSCs in this model as demonstrated by improved learning and memory in the Morris water maze, enhanced neurogenesis and alleviated neural apoptosis in the hippocampus of the AD mice. Moreover, hUC-MSCs and resveratrol jointly regulate expression of hippocampal SIRT1, PCNA, p53, ac-p53, p21, and p16. These data strongly suggests that hUC-MSCs transplantation combined with resveratrol may be an effective therapy for AD.

Topics: Alzheimer Disease; Animals; Cell Differentiation; Disease Models, Animal; Hippocampus; Humans; Memory; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice, Transgenic; Neurogenesis; Neurons; Resveratrol; Stilbenes; Umbilical Cord

Polyhydroxy stilbenes have been reported to possess various biological activities, and have potential in the treatment of Alzheimer's disease (AD). Tetrahydroxystilbene glucoside is one of the major polyhydroxy stilbenes, which provides underlying therapeutic activities for neuroprotective actions in various experimental conditions. This study intends to investigate the impact of tetrahydroxystilbene glucoside remedy for cognitive disorder and oxidative stress in Aβ1-42-induced AD mice and to clarify the mechanisms of action through Keap1/Nrf2 pathway. It was found that The swimming time of Aβ1-42-induced mice which were treated by tetrahydroxystilbene glucoside (30, 60 and 120 mg/kg) was significantly increased in the target quadrant through the Morris water maze experiment and the number of avoidances was increased through the passive avoidance experiment. Moreover, tetrahydroxystilbene glucoside attenuated Aβ1-42-induced memory impairment, however, the locomotor and exploratory activity of the mice were not affected. Tetrahydroxystilbene glucoside obviously decreased the levels of MDA and GSSG in both hippocampus and cortex compared with the Aβ1-42-treated group, and obviously increased the level of GSH and activities of CAT and SOD in above tissues. The results of this study also demonstrated that tetrahydroxystilbene glucoside increased Nrf2 and HO-1 protein expression and decreased Keap1 protein expression in a concentration-dependent manner in Aβ1-42-treated mice, which involved in the Keap1/Nrf2 antioxidant pathway in hippocampus and cerebral cortex tissue. These results demonstrated that tetrahydroxystilbene glucoside as a natural drug might provide potential treatment for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Cerebral Cortex; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Kelch-Like ECH-Associated Protein 1; Learning; Male; Memory; Mice, Inbred ICR; NF-E2-Related Factor 2; Nootropic Agents; Peptide Fragments; Random Allocation; Stilbenes

Accurate amyloid PET quantification is necessary for monitoring amyloid-β accumulation and response to therapy. Currently, most of the studies are analyzed using the static SUV ratio (SUVR) approach because of its simplicity. However, this approach may be influenced by changes in cerebral blood flow (CBF) or radiotracer clearance. Full tracer kinetic models require arterial blood sampling and dynamic image acquisition. The objectives of this work were, first, to validate a noninvasive kinetic modeling approach for

Topics: Aged; Alzheimer Disease; Aniline Compounds; Female; Humans; Kinetics; Male; Models, Biological; Positron-Emission Tomography; Radioactive Tracers; Stilbenes

Alzheimer's disease (AD) is marked by several cellular and molecular damage. Therefore, the therapeutic interest of multi-target molecules is increasingly justified. Polyphenols presenting multiple pharmacological effects would be more efficient. In this study, beneficial effects of trans ε-viniferin, a natural polyphenol were thus evaluated. This study reported that this stilbenoid (1) induced the disaggregation of amyloid β (Aβ) peptide and (2) rescued inflammation in murine primary neuronal cultures. These both effects are higher than those of resveratrol, and so, trans ε-viniferin could be a good therapeutic multi-target candidate.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Benzofurans; Cells, Cultured; Disease Models, Animal; Mice; Neurons; Stilbenes

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animal Feed; Animals; Biomarkers; Brain; Cognitive Dysfunction; Cytokines; Disease Models, Animal; Flavonoids; Fruit; Glycogen Synthase Kinase 3 beta; Male; Mice; Molecular Structure; Peptide Fragments; Phosphorylation; Protein Aggregates; Psoralea; Resveratrol; Stilbenes; tau Proteins

Topics: Alzheimer Disease; Anti-Inflammatory Agents; Blood-Brain Barrier; Cell Line; Central Nervous System; Drug Design; Humans; Interleukin-1beta; MAP Kinase Signaling System; Nitric Oxide; Phosphorylation; Pyrimidines; Stilbenes; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Carbon Radioisotopes; Fluorodeoxyglucose F18; Humans; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes; Thiazoles

A series of pterostilbene β-amino alcohol derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro assays demonstrated that most of the derivatives were selective acetylacholinesterase (AChE) inhibitors with moderate multifunctional properties. Among them, compound 5f exhibited the best inhibitory activity for EeAChE (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amino Alcohols; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Electrophorus; Hydrogen Peroxide; Models, Molecular; Molecular Structure; Neuroprotective Agents; PC12 Cells; Peptide Fragments; Protein Aggregates; Rats; Stilbenes; Structure-Activity Relationship

Inhibiting β-amyloid (Aβ)-induced microglial activation is proposed as an effective strategy for the treatment of Alzheimer's disease. Tetrahydroxystilbene glycoside (TSG) is the main active ingredient of Polygonum multiflorum and has a wide range of biological properties, including antiinflammation. Here, we focused on the function and regulatory mechanism of TSG in Aβ-induced N9 and BV2 cells. The results showed that Aβ treatment induced the activation of microglia cells and the production of inflammatory molecules, including inducible nitric oxide synthase, nitric oxide, cyclooxygenase 2, and prostaglandin E2, which were significantly inhibited by TSG pretreatment. Furthermore, we found Aβ exposure increased the levels of microglial M1 markers, interleukin (IL)-1β, IL-6, and tumor necrosis factor α, and the pretreatment of TSG suppressed the increase of M1 markers and enhanced the levels of M2 markers, including IL-10, brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, and arginase-1. PU.1 overexpression was found to eradicate the anti-inflammatory effects of TSG in Aβ-induced microglial cells. Taken together, these findings indicate that TSG attenuates Aβ-induced microglial activation and polarizes microglia towards M2 phenotype, which may be closely associated with the regulation of PU.1.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Arginase; Brain-Derived Neurotrophic Factor; Cells, Cultured; Glucosides; Inflammation; Interleukin-1beta; Mice; Microglia; NF-kappa B; Nitric Oxide Synthase Type II; Stilbenes; Tumor Necrosis Factor-alpha

We investigated sequential order between tau and amyloid-β (Aβ) deposition in Alzheimer disease spectrum using a conditional probability method. Two hundred twenty participants underwent

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cerebral Cortex; Female; Fluorine Radioisotopes; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes; tau Proteins

Accumulation and oligomerization of amyloid-beta (Aβ) peptides have been known to be a potent cause of neurodegenerative diseases such as Alzheimer's disease (AD). To expand the possibilities of preventing AD, we investigated the effects of resveratrol dimers, gnetin C and ε-viniferin, on Aβ 1-42 (Aβ42) production and the reduced cell viability observed after Aβ42 treatment (monomers, 10 μM) in cultured SH-SY5Y human neuroblastoma cells. Among them, addition of gnetin C (20 μM) into the media reduced Aβ42 production most efficiently. Gnetin C suppressed the expression of β-site amyloid precursor protein-cleaving enzyme-1 (BACE1, β-secretase). Furthermore, gnetin C ameliorated the Aβ42-reduced cell viability most significantly. Concomitantly, gnetin C reduced intracellular Aβ oligomers (ca. 15 and 130 kDa) and elevated both levels of intracellular and extracellular Aβ monomers. Under the treatment with or without Aβ42, gnetin C upregulated the expression of matrix metalloproteinase-14 (MMP-14) which is assumed to be an Aβ-decomposing enzyme. Gnetin C may thereby prevent Aβ toxicity by suppressing BACE1 and enhancing MMP-14, together with reducing both internalization and oligomerization of exogenous Aβ monomers. The use of gnetin C may lead to the prevention of Aβ-mediated diseases, particularly AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzofurans; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Neuroblastoma; Peptide Fragments; Resveratrol; Stilbenes

Depression is a risk factor for mild cognitive impairment (MCI) and for the conversion from MCI to Alzheimer's disease (AD). This study investigated regional cerebral glucose metabolism (rCMglc) in older adults with depression and MCI, either with or without amyloidopathy.. We recruited 31 older adults diagnosed with depression and MCI, and 21 older adults with normal cognition (NC). All participants completed demographic questionnaires and were examined with a standardized neuropsychological battery, F-18 fluorodeoxyglucose positron emission tomography (PET), and F-18 florbetaben PET. We classified subjects with depression and MCI into amyloid-β-positive (CDAP; n = 16) and amyloid-β-negative (CDAN; n = 15) groups. Pairwise rCMglc analyses were conducted between all three groups (CDAP vs. NC, CDAN vs. NC, and CDAP vs. CDAN).. In comparison with the NC group, the CDAP group showed reduced rCMglc predominantly in temporoparietal regions, whereas the CDAN group showed lower rCMglc in regions of the frontal lobe, in addition to the temporoparietal regions. The CDAN group also showed lower rCMglc in right anterior cingulate and left inferior orbitofrontal regions, in a comparison between the CDAP and CDAN groups.. The generalizability of the findings is limited because this study has a relatively small number of participants. In addition, this study used cross-sectional design rather than longitudinal design.. Our findings may provide a reference to assess the risk of future cognitive deterioration. Consequently, this study is expected to contribute to prevention and early identification of dementia associated with AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Cerebral Cortex; Cognitive Dysfunction; Cross-Sectional Studies; Depressive Disorder; Female; Fluorodeoxyglucose F18; Glucose; Humans; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes

Current research diagnostic criteria for Alzheimer's disease (AD) and mild cognitive impairment (MCI) due to AD include biomarkers to supplement clinical testing. Recently, we demonstrated that dual time-point [18F]FBB PET is able to deliver both blood flow and amyloid-β (Aβ) load surrogates.. The aim of this study was to investigate whether these surrogates can be utilized as AD biomarkers.. 112 subjects (41 with MCI, 50 with probable/possible AD, 21 with other dementias) underwent dual time-point [18F]FBB PET. Data were visually and relative quantitatively (Herholz scores for the early and composite SUVRs for the late PET data) analyzed.. In the early images AD-typical patterns were present in 42% /27% /33% of probable/possible AD/MCI/other dementia cases. In late [18F]FBB PET, 42% /29% /38% of probable/possible AD/ MCI/other dementia cases were Aβ-positive. 17% of the MCIs were categorized as "MCI due to AD-high likelihood", 44% of the probable ADs as "probable AD with high evidence of AD pathophysiological process" and 28% of the possible ADs as "possible AD with evidence of AD pathophysiological process". 27% of all subjects showed a positive diagnostic and progression biomarker. Herholz scores were lower (0.85±0.05 versus 0.88±0.04, p = 0.015) for probable/possible AD versus MCI. Composite late phase SUVRs were significantly higher (1.65±0.23 versus 1.15±0.17, p < 0.005) in Aβ-positive versus Aβ-negative patients. Herholz and MMSE scores were positively correlated (R = 0.30 p = 0.006).. Dual time-point [18F]FBB PET provides dual biomarker information which enables to categorize MCI and AD dementia patients according to established diagnostic criteria. Thus, dual time-point [18F]FBB PET has great potential to supplement diagnostic dementia workups.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Biomarkers; Brain; Cognitive Dysfunction; Diagnosis, Differential; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Neuroimaging; Positron-Emission Tomography; Retrospective Studies; Stilbenes

Standardized uptake value ratios (SUVRs) calculated from cerebral cortical areas can be used to categorize. SUVR cutoffs were generated for each RR using FBB scans from 143 subjects who were visually assessed by 3 readers. SUVR cutoffs were validated in 78 end-of life subjects using VA from 8 independent blinded readers (3 expert readers and 5 non-expert readers) and histopathological confirmation of the presence of neuritic beta-amyloid plaques as SoT. Finally, the number of correctly or incorrectly classified scans according to pathology results using VA and SUVR cutoffs was compared.. Composite SUVR cutoffs generated were 1.43 (GCER), 0.96 (WCER), 0.78 (PONS) and 0.71 (SWM). Accuracy values were high and consistent across RR (range 83-94% for histopathology, and 85-94% for VA). SUVR cutoff performed similarly as VA but did not improve VA classification of FBB scans read either by expert readers or the majority read but provided higher accuracy than some non-expert readers.. The accurate scan classification obtained in this study supports the use of VA as SoT to generate site-specific SUVR cutoffs. For an elderly end of life population, VA and SUVR cutoff categorization perform similarly in classifying FBB scans as Aβ-positive or Aβ-negative. These results emphasize the additional contribution that SUVR cutoff classification may have compared with VA performed by non-expert readers.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Brain; Classification; Cohort Studies; Female; Humans; Image Interpretation, Computer-Assisted; Male; Positron-Emission Tomography; Stilbenes; Terminally Ill

A series of prenylated resveratrol derivatives were designed, semisynthesized and biologically evaluated for inhibition of β-secretase (BACE1) and amyloid-β (Aβ) aggregation as well as free radical scavenging and neuroprotective and neuritogenic activities, as potential novel multifunctional agents against Alzheimer's disease (AD). The results showed that compound 4b exhibited good anti-Aβ aggregation (IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Antioxidants; Cell Culture Techniques; Humans; Neurites; Neurons; Neuroprotective Agents; Oxidative Stress; Plant Extracts; Prenylation; Resveratrol; Stilbenes

In the initial evaluation of patients with suspected dementia and Alzheimer's disease, there is no consensus on how to perform semiquantification of amyloid in such a way that it: (1) facilitates visual qualitative interpretation, (2) takes the kinetic behaviour of the tracer into consideration particularly with regard to at least partially correcting for blood flow dependence, (3) analyses the amyloid load based on accurate parcellation of cortical and subcortical areas, (4) includes partial volume effect correction (PVEC), (5) includes MRI-derived topographical indexes, (6) enables application to PET/MRI images and PET/CT images with separately acquired MR images, and (7) allows automation.. Subjects classified visually as amyloid-positive showed a sparse tracer uptake in the primary sensory, motor and visual areas in accordance with the isocortical stage of the topographic distribution of the amyloid plaque (Braak stages V/VI). In patients classified visually as amyloid-negative, the method revealed detectable levels of tracer uptake in the basal portions of the frontal and temporal lobes, areas that are known to be sites of early deposition of amyloid plaques that probably represented early accumulation (Braak stage A) that is typical of normal ageing. There was a strong correlation between age and the indexes of the new dual time-point amyloid imaging method in amyloid-negative patients.. The method can be considered a valuable tool in both routine clinical practice and in the research setting as it will standardize data regarding amyloid deposition. It could potentially also be used to identify early amyloid plaque deposition in younger subjects in whom treatment could theoretically be more effective.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Brain; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Retrospective Studies; Stilbenes; Time Factors

In Alzheimer disease (AD), neuroinflammation is an important process related to the deposition of beta-amyloid plaques and the activation of microglia. The inflammatory process can occur in both the gray matter and the white matter. We evaluated glucose metabolism of the white matter in AD patients and compared the value with cognitive parameters of the patients.Eighteen AD patients and 18 healthy subjects underwent F-18 fluorodeoxyglucose (FDG) and F-18 florbetaben positron emission tomography (PET). After segmentation of the white matter in both PET images, the specific binding ratio (SBR) of the global and regional cerebral white matter was checked. We evaluated the differences in SBR of the global and regional white matter between AD patients and healthy subjects. Then, we assessed the correlation between SBR and cognitive parameters in AD patients.In F-18 FDG PET images, the global white matter SBR was significantly higher in AD patients than in healthy subjects. In the regional analysis, the white matter SBR was significantly higher for the frontal, temporal, and parietal areas in AD patients. In the correlation analysis with F-18 FDG PET, SBR was significantly correlated with the Global Deterioration Scale, Mini-Mental State Examination scores, and amyloid deposition.Glucose metabolism of the white matter was significantly higher in AD patients than in healthy subjects and it was related to the scores of cognitive parameters. We suggest that F-18 FDG PET, like 18-kDa translocator protein PET, could be used as an indicator of neuroinflammation; however, further research is needed for a direct comparison between the 2 tests.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Cognition; Female; Fluorodeoxyglucose F18; Glucose; Humans; Image Processing, Computer-Assisted; Male; Mental Status Schedule; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Retrospective Studies; Stilbenes; White Matter

To optimize magnetic resonance imaging (MRI) of antibody-conjugated superparamagnetic nanoparticles for detecting amyloid-β plaques and activated microglia in a 3X transgenic mouse model of Alzheimer's disease.. Ten 3X Tg mice were fed either chow or chow containing 100 ppm resveratrol. Four brains, selected from animals injected with either anti-amyloid targeted superparamagnetic iron oxide nanoparticles, or anti-Iba-1-conjugated FePt-nanoparticles, were excised, fixed with formalin, and placed in Fomblin for ex vivo MRI (11.7T) using multislice-multiecho, multiple gradient echo, rapid acquisition with relaxation enhancement, and susceptibility-weighted imaging (SWI). Aβ plaques and areas of neuroinflammation appeared as hypointense regions whose number, location, and Z-score were measured as a function of sequence type and echo time.. The MR contrast was due to the shortening of the transverse relaxation time of the plaque-adjacent tissue water. A theoretical analysis of this effect showed that the echo time was the primary determinant of plaque contrast and was used to optimize Z-scores. The Z-scores of the detected lesions varied from 21 to 34 as the echo times varied from 4 to 25 msec, with SWI providing the highest Z-score and number of detected lesions. Computation of the entire plaque and activated microglial distributions in 3D showed that resveratrol treatment led to a reduction of ∼24-fold of Aβ plaque density and ∼4-fold in microglial activation.. Optimized MRI of antibody-conjugated superparamagnetic nanoparticles served to reveal the 3D distributions of both Aβ plaques and activated microglia and to measure the effects of drug treatments in this 3X Tg model.. 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:574-588.

Topics: Alleles; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloidogenic Proteins; Animals; Brain; Contrast Media; Disease Models, Animal; Ferric Compounds; Homozygote; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Magnetite Nanoparticles; Metal Nanoparticles; Mice; Mice, Transgenic; Micelles; Microglia; Mutation; Plaque, Amyloid; Resveratrol; Stilbenes

Today, the use of biomarkers such as amyloid-specific positron emission tomography (PET) tracers and information derived from cerebrospinal fluid (CSF) can support the diagnosis of Alzheimer's disease (AD) as an indicator for the presence of amyloid pathology. We here show that the PET signal of the

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Humans; Middle Aged; Peptide Fragments; Positron-Emission Tomography; Reproducibility of Results; Sensitivity and Specificity; Stilbenes

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

Multi-target drug discovery is one of the most followed approaches in the active central nervous system (CNS) therapeutic area, especially in the search for new drugs against Alzheimer's disease (AD). This is because innovative multi-target-directed ligands (MTDLs) could more adequately address the complexity of this pathological condition. In a continuation of our efforts aimed at a new series of anti-AD MTDLs, we combined the structural features of the cholinesterase inhibitor drug tacrine with that of resveratrol, which is known for its purported antioxidant and anti-neuroinflammatory activities. The most interesting hybrid compounds (5, 8, 9 and 12) inhibited human acetylcholinesterase at micromolar concentrations and effectively modulated Aβ self-aggregation in vitro. In addition, 12 showed intriguing anti-inflammatory and immuno-modulatory properties in neuronal and glial AD cell models. Importantly, the MTDL profile is accompanied by high-predicted blood-brain barrier permeability, and low cytotoxicity on primary neurons.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Drug Design; Humans; Ligands; Liver; Molecular Targeted Therapy; Neuroprotective Agents; Peptide Fragments; Protein Aggregates; Rats; Resveratrol; Stilbenes; Tacrine

The aggregation of amyloid-β peptide (Aβ) has been linked to the formation of neuritic plaques, which are pathological hallmarks of Alzheimer's disease (AD). Various natural compounds have been suggested as therapeutics for AD. Among these compounds, resveratrol has aroused great interest due to its neuroprotective characteristics. Here, we provide evidence that grape skin and grape seed extracts increase the inhibition effect on Aβ aggregation. However, after intravenous injection, resveratrol is rapidly metabolized into both glucuronic acid and sulfate conjugations of the phenolic groups in the liver and intestinal epithelial cells (within less than 2 h), which are then eliminated. In the present study, we show that solid lipid nanoparticles (SLNs) functionalized with an antibody, the anti-transferrin receptor monoclonal antibody (OX26 mAb), can work as a possible carrier to transport the extract to target the brain. Experiments on human brain-like endothelial cells show that the cellular uptake of the OX26 SLNs is substantially more efficient than that of normal SLNs and SLNs functionalized with an unspecific antibody. As a consequence, the transcytosis ability of these different SLNs is higher when functionalized with OX-26.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Drug Compounding; Drug Delivery Systems; Drug Liberation; Grape Seed Extract; Immunoconjugates; Lipids; Nanoparticles; Particle Size; Permeability; Plant Extracts; Protein Aggregates; Protein Aggregation, Pathological; Resveratrol; Stilbenes; Vitis

A series of pyridoxine-resveratrol hybrids Mannich base derivatives as multifunctional agents have been designed, synthesized and evaluated for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activity. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and metal-chelating properties were also tested. The results showed that most of these compounds could selectively inhibit acetylcholinesterase (AChE) and MAO-B. Among them, compounds 7d and 8b exhibited the highest potency for AChE inhibition with IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Chelating Agents; Cholinesterase Inhibitors; Electrophorus; Humans; Kinetics; Mannich Bases; Metals; Models, Molecular; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pyridoxine; Rats; Resveratrol; Stilbenes

Resveratrol is a polyphenol present in red wine for which the capability of directly interfering with the hallmark of Alzheimer's disease (AD), i.e. toxic β-amyloid protein (Aβ) aggregation, has been shown recently. Since the stimulation of proteostasis could explain reduced Aβ-aggregation, we searched for proteostasis targets of resveratrol.. The transgenic Caenorhabditis elegans strain CL2006, expressing Aβ1-42 under control of a muscle-specific promoter and responding to Aβ-toxicity with paralysis, was used as a model. Target identification was accomplished through specific knockdowns of proteostasis genes by RNA interference. Effects of resveratrol on protein aggregation were identified using ProteoStat(®) Detection Reagent, and activation of proteasomal degradation by resveratrol was finally proven using a specific fluorogenic peptide substrate.. Resveratrol at a concentration of 100 µM caused a 40 % decrease in paralysis. UBL-5 involved in unfolded protein response (UPR) in mitochondria proved to be necessary for the prevention of Aβ-toxicity by resveratrol. Also XBP-1, which represents an endoplasmic reticulum-resident factor involved in UPR, was identified to be necessary for the effects of resveratrol. Regarding protein degradation pathways, the inhibition of macroautophagy and chaperone-mediated autophagy prevented resveratrol from reducing paralysis as did the inhibition of proteasomal degradation. Finally, resveratrol reduced the amount of lysosomes, suggesting increased flux of proteins through the autophagy pathways and activated proteasomal degradation.. Resveratrol reduces the Aβ-induced toxicity in a C. elegans model of AD by targeting specific proteins involved in proteostasis and thereby reduces the amount of aggregated Aβ.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Autophagy; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Carrier Proteins; Disease Models, Animal; Endoplasmic Reticulum Stress; Mitochondria; Paralysis; Peptide Fragments; Proteasome Endopeptidase Complex; Proteostasis Deficiencies; Resveratrol; RNA Interference; Stilbenes; Ubiquitins; Unfolded Protein Response

It has been reported that beta amyloid induces production of radical oxygen species and oxidative stress in neuronal cells, which in turn upregulates β-secretase (BACE-1) expression and beta amyloid levels, thereby propagating oxidative stress and increasing neuronal injury. A series of resveratrol derivatives, known to be inhibitors of oxidative stress-induced neuronal cell death (oxytosis) were biologically evaluated against BACE-1 using homogeneous time-resolved fluorescence (TRF) assay. Correlation between oxytosis inhibitory and BACE-1 inhibitory activity of resveratrol derivatives was statistically significant, supporting the notion that BACE-1 may act as pivotal mediator of neuronal cell oxytosis. Four of the biologically evaluated resveratrol analogs demonstrated considerably higher activity than resveratrol in either assay. The discovery of some "hits" led us to initiate detailed docking studies associated with Molecular Dynamics in order to provide a plausible explanation for the experimental results and understand their molecular basis of action.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cell Death; Cell Line; Dose-Response Relationship, Drug; Mice; Molecular Dynamics Simulation; Molecular Structure; Neurons; Oxidative Stress; Resveratrol; Stilbenes; Structure-Activity Relationship

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major component of the plaques, amyloid-β (Aβ), is generated from amyloid-β precursor protein (APP) by β- and γ-secretase-mediated cleavages. Multiple lines of evidence demonstrate that overproduction/accumulation of Aβ in vulnerable brain regions is a primary cause of the pathogenesis of AD. Among the twelve polyphenols isolated from the leaf extracts of Vitis thunbergii var. taiwaniana (VTT), stenophyllol C, stenophyllol B, ampelopsin C, vitisin A, and davidiol A were shown to significantly reduce both Aβ40 and Aβ42 levels in N2a695 cells. Further studies revealed that ampelopsin C and vitisin A reduce Aβ production through inhibiting β-secretase activity, while the effects of the other active polyphenols on reducing Aβ generation are through different mechanisms. These results suggest that VTT extracts may be beneficial for AD prevention and treatment.

Topics: ADAM17 Protein; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cell Line, Tumor; Enzyme Activators; Humans; Mice; Peptide Fragments; Plant Leaves; Polyphenols; Protease Inhibitors; Stilbenes; Vitis

We studied topographic distribution of tau and amyloid-β in a patient with variant Alzheimer's disease with spastic paraparesis (VarAD) by comparing AD patients. The proband developed progressive memory impairment, dysarthria, and spastic paraparesis at age 23. Heterozygous missense mutation (L166P) was found in exon 6 of presenilin-1 gene. The proband showed prominently increased amyloid binding in striatum and cerebellum and asymmetrical tau binding in the primary sensorimotor cortex contralateral to the side more affected by spasticity. We suspect that upper motor neuron dysfunctions may be attributed to excessive abnormal tau accumulation rather than amyloid-β in the primary motor cortex.

Topics: Adult; Aged; Alzheimer Disease; Aniline Compounds; Brain Mapping; Carbolines; Female; Humans; Male; Motor Cortex; Mutation, Missense; Paraparesis, Spastic; Positron-Emission Tomography; Presenilin-1; Radiopharmaceuticals; Stilbenes; tau Proteins

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

Resveratrol, a natural polyphenol found in red wine, has wide spectrum of pharmacological properties including antioxidative and antiaging activities. Beta amyloid peptides (Aβ) are known to involve cognitive impairment, neuroinflammatory and apoptotic processes in Alzheimer's disease (AD). Activation of cAMP and/or cGMP activities can improve memory performance and decrease the neuroinflammation and apoptosis. However, it remains unknown whether the memory enhancing effect of resveratrol on AD associated cognitive disorders is related to the inhibition of phosphodiesterase 4 (PDE4) subtypes and subsequent increases in intracellular cAMP and/or cGMP activities. This study investigated the effect of resveratrol on Aβ1-42-induced cognitive impairment and the participation of PDE4 subtypes related cAMP or cGMP signaling. Mice microinfused with Aβ1-42 into bilateral CA1 subregions displayed learning and memory impairment, as evidenced by reduced memory acquisition and retrieval in the water maze and retention in the passive avoidance tasks; it was also significant that neuroinflammatory and pro-apoptotic factors were increased in Aβ1-42-treated mice. Aβ1-42-treated mice also increased in PDE4A, 4B and 4D expression, and decreased in PKA level. However, PKA inhibitor H89, but not PKG inhibitor KT5823, prevented resveratrol's effects on these parameters. Resveratrol also reversed Aβ1-42-induced decreases in phosphorylated cAMP response-element binding protein (pCREB), brain derived neurotrophic factor (BDNF) and anti-apoptotic factor BCl-2 expression, which were reversed by H89. These findings suggest that resveratrol reversing Aβ-induced learning and memory disorder may involve the regulation of neuronal inflammation and apoptosis via PDE4 subtypes related cAMP-CREB-BDNF signaling.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Cyclic Nucleotide Phosphodiesterases, Type 4; Disease Models, Animal; Male; Memory Disorders; Mice; Mice, Inbred ICR; Peptide Fragments; Phosphodiesterase 4 Inhibitors; Resveratrol; Signal Transduction; Stilbenes

[(18)F]FDG is a commonly used neuronal injury biomarker for early and differential diagnosis of dementia. Typically, the blood supply to the brain is closely coupled to glucose consumption. Early uptake of the Aβ tracer [(11)C]PiB on PET images is mainly determined by cerebral blood flow and shows a high correlation with [(18)F]FDG uptake. Uptake data for (18)F-labelled Aβ PET tracers are, however, scarce. We investigated the value of early PET images using the novel Aβ tracer [(18)F]FBB in the diagnosis of Alzhimers disease (AD).. This retrospective analysis included 22 patients with MCI or dementia who underwent dual time-point PET imaging with either [(11)C]PiB (11 patients) or [(18)F]FBB (11 patients) in routine clinical practice. Images were acquired 1 - 9 min after administration of both tracers and 40 - 70 min and 90 - 110 min after administration of [(11)C]PiB and [(18)F]FBB, respectively. The patients also underwent [(18)F]FDG brain PET imaging. PET data were analysed visually and semiquantitatively. Associations between early Aβ tracer uptake and dementia as well as brain atrophy were investigated.. Regional visual scores of early Aβ tracer and [(18)F]FDG PET images were significantly correlated (Spearman's ρ = 0.780, P < 0.001). Global brain visual analysis revealed identical results between early Aβ tracer and [(18)F]FDG PET images. In a VOI-based analysis, the early Aβ tracer data correlated significantly with the [(18)F]FDG data (r = 0.779, P < 0.001), but there were no differences between [(18)F]FBB and [(11)C]PiB. Cortical SUVRs in regions typically affected in AD on early Aβ tracer and [(18)F]FDG PET images were correlated with MMSE scores (ρ = 0.458, P = 0.032, and ρ = 0.456, P = 0.033, respectively). A voxel-wise group-based search for areas with relatively higher tracer uptake on early Aβ tracer PET images compared with [(18)F]FDG PET images revealed a small cluster in the midbrain/pons; no significant clusters were found for the opposite comparison.. Early [(18)F]FBB and [(11)C]PiB PET brain images are similar to [(18)F]FDG PET images in AD patients, and these tracers could potentially be used as biomarkers in place of [(18)F]FDG. Thus, Aβ tracer PET imaging has the potential to provide biomarker information on AD pathology and neuronal injury. The potential of this approach for supporting the diagnosis of AD needs to be confirmed in prospective studies in larger cohorts.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Biological Transport; Female; Hippocampus; Humans; Male; Middle Aged; Neurons; Positron-Emission Tomography; Stilbenes; Thiazoles; Time Factors

The highly rigid and planar scaffold with π-conjugated systems has been widely considered to be indispensable for Aβ binding probes. However, the flexible benzyloxybenzene derivative [(125)I]BOB-4 represents an excellent lead candidate for targeting Aβ in AD brains. Based on that, we designed two pairs of more flexible and optically pure diphenoxy derivatives with a chiral center as novel Aβ probes. These compounds possessed high affinity (Ki = 15.8-45.0 nM) for Aβ1-42 aggregates, and (R)-enantiomers showed slightly better binding ability than (S)-enantiomers. In addition, the competition binding assay implied that the optically pure diphenoxy derivatives with more flexible geometry shared the same binding site as IMPY, a classical rigid and planar Aβ probe. For (125)I-radiolabeled enantiomers, (S)-[(125)I]5 and (R)-[(125)I]5, specific plaque labeling on brain sections of Tg mice and AD patients were observed in in vitro autoradiography, persuasively proving the excellent affinity of the probes. In biodistribution, (S)-[(125)I]5 and (R)-[(125)I]5 with relatively low lipophilicity exhibited moderate initial brain uptake (4.37% and 3.72% ID/g at 2 min, respectively) and extremely fast washout from normal mice brain (brain2min/brain60min = 19.0 and 17.7, respectively). In summary, the separate enantiomers displayed similar properties in vitro and in vivo, and (S/R)-[(123)I]5 may be potential SPECT probes for recognizing Aβ plaques in AD brains.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Autoradiography; Brain; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Magnetic Resonance Imaging; Mice; Mice, Inbred ICR; Mice, Transgenic; Peptide Fragments; Plaque, Amyloid; Protein Binding; Pyridines; Stilbenes; Thyroid Gland; Tissue Distribution

To investigate the topographical distribution of tau pathology and its effect on functional and structural changes in patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) by using (18)F-AV-1451 PET.. We included 20 patients with AD, 15 patients with MCI, and 20 healthy controls, and performed neuropsychological function tests, MRI, as well as (18)F-florbetaben (for amyloid) and (18)F-AV-1451 (for tau) PET scans. By using the regional volume-of-interest masks extracted from MRIs, regional binding values of standardized uptake value ratios and volumes were measured. We compared regional binding values among 3 diagnostic groups and identified correlations among the regional binding values, performance in each cognitive function test, and regional atrophy.. (18)F-AV-1451 binding was increased only in the entorhinal cortex in patients with MCI, while patients with AD exhibited greater binding in most cortical regions. In the 35 patients with MCI and AD, (18)F-AV-1451 binding in most of the neocortex increased with a worsening of global cognitive function. The visual and verbal memory functions were associated with the extent of (18)F-AV-1451 binding, especially in the medial temporal regions. The (18)F-AV-1451 binding also correlated with the severity of regional atrophy of the cerebral cortex.. Tau PET imaging with (18)F-AV-1451 could serve as an in vivo biomarker for the evaluation of AD-related tau pathology and monitoring disease progression. The accumulation of pathologic tau is more closely related to functional and structural deterioration in the AD spectrum than β-amyloid.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Cognitive Dysfunction; Disease Progression; Entorhinal Cortex; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Memory; Neuropsychological Tests; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Stilbenes; tau Proteins; Vision, Ocular

Topics: Africa; Aging; Alzheimer Disease; Amyloid; Animal Feed; Animal Husbandry; Animals; Animals, Laboratory; Breeding; Caloric Restriction; CRISPR-Cas Systems; Crosses, Genetic; Disease Models, Animal; Female; Fundulidae; Genetic Engineering; Genomics; Iron; Life Cycle Stages; Longevity; Male; Mice; Models, Animal; Neurosciences; Resveratrol; Stilbenes; Time Factors

Brain amyloid burden may be quantitatively assessed from positron emission tomography imaging using standardised uptake value ratios. Using these ratios as an adjunct to visual image assessment has been shown to improve inter-reader reliability, however, the amyloid positivity threshold is dependent on the tracer and specific image regions used to calculate the uptake ratio. To address this problem, we propose a machine learning approach to amyloid status classification, which is independent of tracer and does not require a specific set of regions of interest. Our method extracts feature vectors from amyloid images, which are based on histograms of oriented three-dimensional gradients. We optimised our method on 133

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Carbon Radioisotopes; Ethylene Glycols; Female; Humans; Image Interpretation, Computer-Assisted; Male; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Stilbenes; Support Vector Machine

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disease that slowly destroys memory and thinking skills. It is the most common cause of dementia among older people. One of the most important hallmarks of AD is the presence of amyloid beta (Aβ) peptide in the brain that suggests that it is the primary trigger for neuronal loss. Herbal extracts have been studied over the years for their potential therapeutic effect in AD. Resveratrol (RSV), one of the most important phytoestrogens, is considered to be useful as estrogen plays an important role in AD. One of the most important amyloid degrading enzymes is neprilysin (NEP), which plays a major role in degrading Aβ, and mainly affected by estrogen. So, the aim of the present study is investigating the possible role of resveratrol in lipopolysaccharide model of AD and the implication of its possible role in regulating the estradiol and neprilysin pathways. Mice were divided into four groups: Control group (0.9 % saline), LPS group (0.8 mg/kg i.p once), Treatment group with RSV (mice were once injected with LPS then after 30 min given a dose of {4 mg/kg} RSV for 7 days), and RSV group only (mice received 4 mg/kg i.p for 7 days only). After 7 days mice were subjected to different behavioral tests using Y-maze, object recognition test, and open field tests. Estradiol and NEP level were measured using ELISA kit. Results showed RSV was able to reverse the decline in different types of memory (working, nonspatial, and locomotor functions) caused by LPS induction in mice. Moreover RSV was able to significantly increase both the estradiol level and NEP level and that may have a great role to decrease Aβ deposition as it has been confirmed that there is a link between NEP and estradiol level; by upregulation of estradiol level this consequently leads to increase in the level of NEP level, and by increasing the NEP level in brain, this lead to decrease in Aβ deposition and enhancing its degradation by NEP.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antineoplastic Agents, Phytogenic; Disease Models, Animal; Estradiol; Lipopolysaccharides; Memory; Mice; Motor Activity; Neprilysin; Random Allocation; Resveratrol; Signal Transduction; Stilbenes; Treatment Outcome

A series of new 2-arylethenylquinoline derivatives (4a1-4a12, 4b1-4b8, 4c1-4c4, 4d1-4d3 and 4e1-4e9) were designed, synthesized, and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro studies showed that these synthetic compounds inhibited self-induced Aβ1-42 aggregation effectively ranged from 23.6% to 83.9% at the concentration of 20 μM, and acted as potential antioxidants and biometal chelators. Their structure-activity relationships were obtained and discussed. In particular, compound 4b1, the most active compound, displayed strong inhibitory activity with an IC50 value of 9.7 μM for self-induced Aβ1-42 aggregation, good antioxidative activity with a value of 3.9-fold of Trolox, potent inhibitory activity for cholinesterase with IC50 values of 0.2 μM and 64.1 μM against butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE), respectively. Besides, 4b1 was also capable of disassembling the self-induced Aβ1-42 aggregation fibrils with a ratio of 59.8% at 20 μM concentration, and had a good metal chelating activity. Taken together, these results suggest that compound 4b1 might be a promising lead compound for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Cell Line, Tumor; Cell Survival; Chelating Agents; Cholinesterase Inhibitors; Drug Design; Humans; Molecular Structure; Peptide Fragments; Quinolines; Stilbenes

Accumulation and deposition of amyloid-β peptide (Aβ) in the brain is a primary cause of the pathogenesis of Alzheimer's disease (AD). Aβ is generated from amyloid-β precursor protein (APP) through sequential cleavages first by β-secretase and then by γ-secretase. Inhibiting β-secretase activity is believed to be one of the most promising strategies for AD treatment. In the present study, we found that a resveratrol trimer, miyabenol C, isolated from stems and leaves of the small-leaf grape (Vitisthunbergii var. taiwaniana), can markedly reduce Aβ and sAPPβ levels in both cell cultures and the brain of AD model mice. Mechanistic studies revealed that miyabenol C affects neither protein levels of APP, the two major α-secretases ADAM10 and TACE, and the γ-secretase component Presenilin 1, nor γ-secretase-mediated Notch processing and TACE activity. In contrast, although miyabenol C has no effect on altering protein levels of the β-secretase BACE1, it can inhibit both in vitro and in vivo β-secretase activity. Together, our results indicate that miyabenol C is a prominent β-secretase inhibitor and lead compound for AD drug development.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Benzofurans; Brain; Cell Line, Tumor; Enzyme Activation; Humans; Mice; Mice, Transgenic; Plant Extracts; Proteolysis; Solubility; Stilbenes

The aim of this study was to compare [(11)C]Pittsburgh compound B ([(11)C]PiB) and [(18)F]florbetaben ([(18)F]FBB) for preclinical investigations of amyloid-β pathology.. We investigated two aged animal models of cerebral amyloidosis with contrasting levels of amyloid-β relating to "high" (APPPS1-21 n = 6, wild type (WT) n = 7) and "low" (BRI1-42 n = 6, WT n = 6) target states, respectively.. APPPS1-21 mice (high target state) demonstrated extensive fibrillar amyloid-β deposition that translated to significantly increased retention of [(11)C]PiB and [(18)F]FBB in comparison to their wild type. The retention pattern of [(11)C]PiB and [(18)F]FBB in this cohort displayed a significant correlation. However, the relative difference in tracer uptake between diseased and healthy mice was substantially higher for [(11)C]PiB than for [(18)F]FBB. Although immunohistochemistry confirmed the high plaque load in APPPS1-21 mice, correlation between tracer uptake and ex vivo quantification of amyloid-β was poor for both tracers. BRI1-42 mice (low target state) did not demonstrate increased tracer uptake.. In cases of high fibrillar amyloid-β burden, both tracers detected significant differences between diseased and healthy mice, with [(11)C]PiB showing a larger dynamic range.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Disease Models, Animal; Immunohistochemistry; Mice; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes; Thiazoles

We aimed to compare [18F]-florbetaben PET imaging in four transgenic mouse strains modelling Alzheimer's disease (AD), with the main focus on APPswe/PS2 mice and C57Bl/6 mice serving as controls (WT). A consistent PET protocol (N = 82 PET scans) was used, with cortical standardized uptake value ratio (SUVR) relative to cerebellum as the endpoint. We correlated methoxy-X04 staining of β-amyloid with PET results, and undertook ex vivo autoradiography for further validation of a partial volume effect correction (PVEC) of PET data. The SUVR in APPswe/PS2 increased from 0.95±0.04 at five months (N = 5) and 1.04±0.03 (p<0.05) at eight months (N = 7) to 1.07±0.04 (p<0.005) at ten months (N = 6), 1.28±0.06 (p<0.001) at 16 months (N = 6) and 1.39±0.09 (p<0.001) at 19 months (N = 6). SUVR was 0.95±0.03 in WT mice of all ages (N = 22). In APPswe/PS1G384A mice, the SUVR was 0.93/0.98 at five months (N = 2) and 1.11 at 16 months (N = 1). In APPswe/PS1dE9 mice, the SUVR declined from 0.96/0.96 at 12 months (N = 2) to 0.91/0.92 at 24 months (N = 2), due to β-amyloid plaques in cerebellum. PVEC reduced the discrepancy between SUVR-PET and autoradiography from -22% to +2% and increased the differences between young and aged transgenic animals. SUVR and plaque load correlated highly between strains for uncorrected (R = 0.94, p<0.001) and PVE-corrected (R = 0.95, p<0.001) data. We find that APPswe/PS2 mice may be optimal for longitudinal amyloid-PET monitoring in planned interventions studies.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Brain; Cross-Sectional Studies; Disease Models, Animal; Mice; Mice, Transgenic; Plaque, Amyloid; Positron-Emission Tomography; Stilbenes

We investigated the effects of 4-17 month supplementation with ω-3 fatty acids and antioxidants (Smartfish drink; Smartfish AS, Oslo, Norway) in 12 patients with minor cognitive impairment (MCI) [minimental state examination (MMSE) ≥19], 2 patients with pre-MCI (normal MMSE), and 7 patients with Alzheimer disease (AD) (MMSE <19). We measured the phagocytosis of amyloid-β 1-42 (Aβ) by flow cytometry and microscopy, the transcription of inflammatory genes by RT-PCR, the production of resolvin D1 (RvD1) by enzyme immunoassay, and the cognitive status by MMSE. In patients with MCI and pre-MCI, phagocytosis of Aβ by monocytes increased from 530 to 1306 mean fluorescence intensity units (P = 0.016). The increase in patients with AD was not significant (N.S.). The lipidic mediator RvD1, which stimulates Aβ phagocytosis in vitro, increased in macrophages in 80% of patients with MCI and pre-MCI (mean increase 9.95 pg/ml) (N.S.). Transcription of inflammatory genes' mRNAs was increased in a subgroup of patients with low transcription at baseline, whereas it was not significantly changed in patients with high transcription at baseline. The mean MMSE score of patients with MCI and pre-MCI was 25.9 at baseline and 25.7 after 4-17 months (N.S.). Our study is the first to show significant immune and biochemical effects of ω-3 fatty acids with antioxidants in patients with MCI. Cognitive benefits of ω-3 supplementation in patients with MCI should be tested in a clinical trial.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Cholecalciferol; Cognitive Dysfunction; Dietary Supplements; Docosahexaenoic Acids; Fatty Acids, Omega-3; Female; Humans; Inflammation; Macrophages; Male; Mental Status Schedule; Middle Aged; Monocytes; Phagocytosis; Resveratrol; RNA, Messenger; Stilbenes

In a positron-emission tomography (PET) study with the β-amyloid (Aβ) tracer [(18)F]-florbetaben, we previously showed that Aβ deposition in transgenic mice expressing Swedish mutant APP (APP-Swe) mice can be tracked in vivo. γ-Secretase modulators (GSMs) are promising therapeutic agents by reducing generation of the aggregation prone Aβ42 species without blocking general γ-secretase activity. We now aimed to investigate the effects of a novel GSM [8-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine (RO5506284) displaying high potency in vitro and in vivo on amyloid plaque burden and used longitudinal Aβ-microPET to trace individual animals. Female transgenic (TG) APP-Swe mice aged 12 months (m) were assigned to vehicle (TG-VEH, n=12) and treatment groups (TG-GSM, n=12), which received daily RO5506284 (30 mg kg(-1)) treatment for 6 months. A total of 131 Aβ-PET recordings were acquired at baseline (12 months), follow-up 1 (16 months) and follow-up 2 (18 months, termination scan), whereupon histological and biochemical analyses of Aβ were performed. We analyzed the PET data as VOI-based cortical standard-uptake-value ratios (SUVR), using cerebellum as reference region. Individual plaque load assessed by PET remained nearly constant in the TG-GSM group during 6 months of RO5506284 treatment, whereas it increased progressively in the TG-VEH group. Baseline SUVR in TG-GSM mice correlated with Δ%-SUVR, indicating individual response prediction. Insoluble Aβ42 was reduced by 56% in the TG-GSM versus the TG-VEH group relative to the individual baseline plaque load estimates. Furthermore, plaque size histograms showed differing distribution between groups of TG mice, with fewer small plaques in TG-GSM animals. Taken together, in the first Aβ-PET study monitoring prolonged treatment with a potent GSM in an AD mouse model, we found clear attenuation of de novo amyloidogenesis. Moreover, longitudinal PET allows non-invasive assessment of individual plaque-load kinetics, thereby accommodating inter-animal variations.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aniline Compounds; Animals; Case-Control Studies; Cerebral Amyloid Angiopathy; Disease Models, Animal; Female; Longitudinal Studies; Mice; Mice, Inbred C57BL; Mice, Transgenic; Plaque, Amyloid; Positron-Emission Tomography; Stilbenes

To observe the effect of tetrahydroxy stilbene glucoside (TSG) on the behavior of APP695V717I transgenic mouse models and the expression of autophagy-associated proteins Beclin-1 and LC3-II.. Forty 3-month-old APP695V717I transgenic mice were randomized equally into either a TSG group (n = 20) or a model group (n = 20). A normal control group consisted of C57BL/6J mice of the same age and background (n = 20). The TSG group received TSG intragastric administration for 1 month. Behavior was measured using the Morris water maze and the Y-maze tests. Changes in pro- tein expression and mRNA of autophagy-associated Beclin-1 and LC3-II in mice hippocampus were detected by western blot and Reverse Transcription-Polymerase Chain Reaction (RT-PCR) analyses.. The number of electric-stimulus escapes significantly increased and the Morris water maze test showed prolonged escape latency, greater swimming distance, less time taken to cross the exact former platform location in the model group, and increased mRNA and protein expressions of Beclin-1 and LC3-II compared with the control group (P < 0.05). The TSG group showed a decrease in the number of electric-stimulus escapes, shorter escape latency and swimming distance, greater time taken to cross the exact former platform location, and decreased mRNA and protein expressions of Beclin-1 and LC3-II compared with the model group (P < 0.05).. these results indicate that tetrahydroxy stilbene glucoside can decrease expressions of Beclin-1 and LC3-II in the autophagy pathway. It can attenuate injury to endoplasmic reticulum functions caused by Ab neurotoxicity, improving learning, memorizing, and spatial orientation behavior in mice.

Topics: Alzheimer Disease; Animals; Apoptosis Regulatory Proteins; Beclin-1; Behavior, Animal; Disease Models, Animal; Female; Glucosides; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubule-Associated Proteins; Stilbenes

Our previous studies demonstrated resveratrol (Res) administration protected Alzheimer's disease (AD) rats from developing memory decline by anti-oxidation. Beta-amyloid peptide 1-42 (Aβ1-42) is not only the primary protein component of senile plaques in AD but also is believed to play an important part in its pathology. Increasing evidence has shown neuroinflammation and the integrity of the blood-brain barrier (BBB) is closely related to the pathogenesis of AD. The aim of the present study is to further elucidate whether Res prevents AD rats from inflammation induced by Aβ1-42 and protects the integrity of BBB. Rats were divided into six groups: (1) ovariectomized (OVX)+D-galactose (D-gal) 100mg/kg group (OVX+D-gal); (2-4) OVX, D-gal and Res 20, 40 and 80 mg/kg treated groups; and (5) OVX, D-gal and estradiol valerate 0.8 mg/kg treated group (ET); (6) Sham control group. 12 weeks later, Res 40 and 80 mg/kg treatment exhibited a significant decrease of Aβ1-42 compared with the OVX+D-gal rats of hippocampus, which was accompanied by decreased expression of advanced glycation endproducts (RAGE), matrix metalloprotein-9 (MMP-9), nuclear factor kappaB (NF-κB) and the increase of Claudin-5. These results suggest that Res is useful not only in protecting OVX+D-gal rats from neuroinflammation mediated by Aβ1-42 by decreasing the expression of NF-κB but also the integrity of BBB by increasing Claudin-5 and decreasing RAGE, MMP-9.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Blood-Brain Barrier; Claudin-5; Disease Models, Animal; Female; Galactose; Glycation End Products, Advanced; Hippocampus; Matrix Metalloproteinase 9; Ovariectomy; Peptide Fragments; Rats; Rats, Wistar; Resveratrol; Stilbenes; Transcription Factor RelA

To explore the effects of resveratrol on astrocyte and TNF-α in hippocampus of Alzheimer's disease (AD) model rats.. Sixty rats were randomly divided into six groups: sham control group, model group, resveratrol 20, 40, 80 mg/kg group, and estradiol valerate group (0.8 mg/kg). The model of AD was established by ovariectomy combined injection of D-galactose (100 mg/kg). Twelve weeks later, the heart perfusion in vivo was done and then the hippocampus was fixed. Additionally, the changes of hippocampal astrocytes and TNF-α expression were detected by immunohistochemistry.. The levels of glial fibrillary acidic protein (GFAP) and TNF-α in the model group were significantly higher than those of the sham control group (P < 0.01). No marked difference in the production of GFAP was observed between the resveratrol 20 mg/kg group and the model group (P > 0.05). However, the resveratrol 40, 80 mg/kg and estradiol valerate treated groups showed a decrease in the expression of GFAP compared with the model group (P < 0.01). Moreover, with the increasing of resveratrol concentration, the expression of GFAP decreased gradually. The levels of TNF-α decreased markedly in Res 20, 40, 80 mg/kg and estradiol valerate group compared with the model group (P < 0.01).. These results suggest that the activation of astrocytes and the secretion of TNF-α can be inhibited by Res in AD rats.

Topics: Alzheimer Disease; Animals; Astrocytes; Disease Models, Animal; Estradiol; Female; Galactose; Glial Fibrillary Acidic Protein; Hippocampus; Humans; Ovariectomy; Rats; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

Amyloid precursor protein (APP) has been modified by β and γ-secretase that cause amyloid deposits (plaques) in neuronal cells. Glyceraldhyde-derived AGEs has been identified as a major source of neurotoxicity in Alzheimer's disease (AD). In a previous study, we demonstrated that glyceraldehyde-derived AGEs increase APP and Aβ via ROS. Furthermore, the combination of AGEs and Aβ has been shown to enhance neurotoxicity. In mice, APP expression is increased by tail vein injection of AGEs. This evidence suggests a correlation between AGEs and the development of AD. However, the role played by AGEs in the pathogenesis of AD remains unclear. In this report, we demonstrate that AGEs up-regulate APP processing protein (BACE and PS1) and Sirt1 expression via ROS, but do not affect the expression of downstream antioxidant genes HO-1 and NQO-1. Moreover, we found that AGEs increase GRP78 expression and enhance the cell death-related pathway p53, bcl-2/bax ratio, caspase 3. These results indicate that AGEs impair the neuroprotective effects of Sirt1 and lead to neuronal cell death via ER stress. Our findings suggest that AGEs increase ROS production, which stimulates downstream pathways related to APP processing, Aβ production, Sirt1, and GRP78, resulting in the up-regulation of cell death related pathway. This in-turn enhances neuronal cell death, which leads to the development of AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Antioxidants; Aspartic Acid Endopeptidases; Caspase 3; Cell Death; Cell Line, Tumor; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Gene Expression Regulation; Glycation End Products, Advanced; Heat-Shock Proteins; Humans; Neurons; Neuroprotective Agents; Plaque, Amyloid; Presenilin-1; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Resveratrol; Sirtuin 1; Stilbenes; Tumor Suppressor Protein p53; Up-Regulation

Alzheimer's disease (AD) is characterized by intraneuronal β-amyloid plaques and hyperphosphorylated tau, leading to neuronal cell death and progressive memory losses. This exploratory work investigates if dietary resveratrol, previously shown to have broad anti-aging effects and improve AD pathology in vivo, leads to neuroprotective changes in specific protein targets in the mouse brain. Both wild-type and APP/PS1 mice, a transgenic AD mouse model, received control AIN-93G diet or AIN-93G supplemented with resveratrol. Pathology parameters and AD risk were assessed via measurements on plaque burden, levels of phosphorylated glycogen synthase kinase 3-β (GSK3-β), tau, transthyretin and drebrin. Dietary resveratrol treatment did not decrease plaque burden in APP/PS1 mice. However, resveratrol-fed mice demonstrated increases in GSK3-β phosphorylation, a 3.8-fold increase in protein levels of transthyretin, and a 2.2-fold increase in drebrin. This study broadens our understanding of specific mechanisms and targets whereby resveratrol provides neuroprotection.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cerebrum; Dietary Supplements; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Male; Mice; Mice, Transgenic; Mutant Chimeric Proteins; Mutation; Nerve Tissue Proteins; Neurons; Neuropeptides; Neuroprotective Agents; Phosphorylation; Prealbumin; Presenilin-1; Protein Processing, Post-Translational; Recombinant Proteins; Resveratrol; Specific Pathogen-Free Organisms; Stilbenes

We previously investigated the progression of β-amyloid deposition in brain of mice over-expressing amyloid-precursor protein (APP-Swe), a model of Alzheimer's disease (AD), in a longitudinal PET study with the novel β-amyloid tracer [(18)F]-florbetaben. There were certain discrepancies between PET and autoradiographic findings, which seemed to arise from partial volume effects (PVE). Since this phenomenon can lead to bias, most especially in the quantitation of brain microPET studies of mice, we aimed in the present study to investigate the magnitude of PVE on [(18)F]-florbetaben quantitation in murine brain, and to establish and validate a useful correction method (PVEC). Phantom studies with solutions of known radioactivity concentration were performed to measure the full-width-at-half-maximum (FWHM) resolution of the Siemens Inveon DPET and to validate a volume-of-interest (VOI)-based PVEC algorithm. Several VOI-brain-masks were applied to perform in vivo PVEC on [(18)F]-florbetaben data from C57BL/6(N=6) mice, while uncorrected and PVE-corrected data were cross-validated with gamma counting and autoradiography. Next, PVEC was performed on longitudinal PET data set consisting of 43 PET scans in APP-Swe (13-20months) and age-matched wild-type (WT) mice using the previously defined masks. VOI-based cortex-to-cerebellum ratios (SUVR) were compared for uncorrected and PVE-corrected results. Brains from a subset of transgenic mice were ultimately examined by autoradiography ex vivo and histochemistry in vitro as gold standard assessments, and compared to VOI-based PET results. The phantom study indicated a FWHM of 1.72mm. Applying a VOI-brain-mask including extracerebral regions gave robust PVEC, with increased precision of the SUVR results. Cortical SUVR increased with age in APP-Swe mice compared to baseline measurements (16months: +5.5%, p<0.005; 20months: +15.5%, p<0.05) with uncorrected data, and to a substantially greater extent with PVEC (16months: +12.2% p<0.005; 20months: +36.4% p<0.05). WT animals showed no binding changes, irrespective of PVEC. Relative to autoradiographic results, the error [%] for uncorrected cortical SUVR was 18.9% for native PET data, and declined to 4.8% upon PVEC, in high correlation with histochemistry results. We calculate that PVEC increases by 10% statistical power for detecting altered [(18)F]-florbetaben uptake in aging APP-Swe mice in planned studies of disease modifying treatments on amyloidogenesis.

Topics: Algorithms; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Autoradiography; Brain; Disease Models, Animal; Fluorine Radioisotopes; Humans; Image Processing, Computer-Assisted; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phantoms, Imaging; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes

Alzheimer's disease is characterized by two notorious protein aggregates in the brain: extracellular senile plaques mainly consisting of amyloid-β peptides and tau-protein-derived intracellular paired helical filaments. The diagnosis of Alzheimer's disease is impaired by insufficient sensitivity and specificity of diagnostic methods to visualize these pathological hallmarks over all disease stages.. The established fluorescence marker methoxy-X04 stains plaques, tau tangles and amyloid-derived angiopathies with good specificity, yet it is limited by slow elimination in vivo. Since the need for new markers is high, we prepared methoxy-X04 derivatives and evaluated their potential as imaging agents in Alzheimer's disease pathology.. In this study, we describe an improved synthesis for methoxy-X04 and its derivatives and their affinity determination for the respective protein targets by immunohistology and a displacement assay.. This resulted in the identification of new derivatives of methoxy-X04 with improved binding affinity.

Topics: Alkenes; Alzheimer Disease; Benzene Derivatives; Humans; Stilbenes

A series of imine resveratrol derivatives (1-20) have been designed, synthesized, and evaluated as multi-targeted compounds for the treatment of Alzheimer's disease (AD). In vitro studies show that most of the molecules exhibit a significant ability to inhibit self-induced and Cu(2+)-induced β-amyloid (Aβ₁₋₄₂) aggregation, and to function as potential antioxidants and biometal chelators. In particular, compound 9 is a potential lead compound for AD treatment (for compound 9, IC₅₀ = 14.1 μM for the antioxidant activity using DPPH free radical method; 64.6% at 20 μM for self-induced Aβ aggregation). Moreover, it is capable of decreasing reactive oxygen species (ROS) induced by Cu-Aβ and shows good neuroprotective effects in human SH-SY5Y neuroblastoma cells. Taken together, these results suggest that 9 might be a promising lead compound for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Cell Line, Tumor; Copper; Humans; Neuroprotective Agents; Reactive Oxygen Species; Resveratrol; Stilbenes

Alzheimer's disease (AD) is associated with a microglia-dependent neuroinflammatory response against plaques containing the fibrous protein amyloid-β (Aβ). Activation of microglia, which closely associate with Aβ plaques, engenders the release of pro-inflammatory cytokines and the internalization of Aβ fibrils. Since the pro-inflammatory transcription factor NF-κB is one of the major regulators of Aβ-induced inflammation, we treated transgenic amyloid-β protein protein/presenilin-1 (AβPP/PS1) mice for one year with a low dose (0.01% by weight in the diet) of either of two trans-stilbene NF-κB inhibitors, resveratrol or a synthetic analog LD55. The 3D distribution of Aβ plaques was measured ex vivo in intact brains at 60 μm resolution by quantitative magnetic resonance imaging (MRI) using blood-brain barrier-permeable, anti-AβPP-conjugated superparamagentic iron oxide nanoparticles (SPIONs). The MRI measurements were confirmed by optical microscopy of thioflavin-stained brain tissue sections and indicated that supplementation with either of the two trans-stilbenes lowered Aβ plaque density in the cortex, caudoputamen, and hippocampus by 1.4 to 2-fold. The optical measurements also included the hippocampus and indicated that resveratrol and LD55 reduced average Aβ plaque density by 2.3-fold and 3.1-fold, respectively. Ex vivo measurements of the regional distribution of microglial activation by Iba-1 immunofluorescence of brain tissue sections showed that resveratrol and LD55 reduced average microglial activation by 4.2- fold and 3.5-fold, respectively. Since LD55 lacked hydroxyl groups but both resveratrol and LD55 concomitantly reduced both Aβ plaque burden and neuroinflammation to a similar extent, it appears that the antioxidant potential of resveratrol is not an important factor in plaque reduction.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Disease Models, Animal; Enzyme Inhibitors; Ferric Compounds; Humans; Imaging, Three-Dimensional; Metal Nanoparticles; Mice; Mice, Transgenic; Microglia; Mutation; Neuroprotective Agents; NF-kappa B; Plaque, Amyloid; Presenilin-1; Resveratrol; Stilbenes

Developing an effective means for the real-time probing of amyloid β (Aβ) that is closely implicated in Alzheimer's disease (AD) could help better understand and monitor the disease. Here we describe an economic approach based on the simple composition of a natural product, resveratrol (Res), with graphene oxide (GO) for the rapid, fluorogenic recognition of Aβ. The Res@GO composite has proved specific for Aβ over a range of proteins and ions, and could sensitively capture both Aβ monomers and fibers in a physiological buffer solution within only 3 min. The composite can also fluorescently image amyloid deposits in a mouse brain section within 30 min. This new protocol is much cheaper and more timesaving than the conventional immunofluorescence staining technique employed clinically, providing an economic tool for the concise detection of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Fluorescence; Fluorescent Antibody Technique; Graphite; Humans; Mice; Resveratrol; Stilbenes

Alzheimer's disease (AD) is currently one of the most difficult and challenging diseases to treat. Based on the ‘multi-target-directed ligands’ (MTDLs) strategy, we designed and synthesised a series of new compounds against AD by combining the pharmacophores of resveratrol and clioquinol. The results of biological activity tests showed that the hybrids exhibited excellent MTDL properties: a significant ability to inhibit self-induced β-amyloid (Aβ) aggregation and copper(II)-induced Aβ aggregation, potential antioxidant behaviour (ORAC-FL value of 0.9–3.2 Trolox equivalents) and biometal chelation. Among these compounds, (E)-5-(4-hydroxystyryl)quinoline-8-ol (10c) showed the most potent ability to inhibit self-induced Aβ aggregation (IC50 = 8.50 μM) and copper(II)-induced Aβ aggregation and to disassemble the well-structured Aβ fibrils generated by self- and copper(II)-induced Aβ aggregation. Note that 10c could also control Cu(I/II)-triggered hydroxyl radical (OH˙) production by halting copper redox cycling via metal complexation, as confirmed by a Cu–ascorbate redox system assay. Importantly, 10c did not show acute toxicity in mice at doses of up to 2000 mg kg−1 and was able to cross the blood–brain barrier (BBB), according to a parallel artificial membrane permeation assay. These results indicate that compound 10c is a promising multifunctional compound for the development of novel drugs for AD.

Topics: Absorption, Physiological; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Chelating Agents; Clioquinol; Copper; Drug Design; Hydroxyl Radical; Mice; Oxidation-Reduction; Permeability; Protein Aggregates; Resveratrol; Small Molecule Libraries; Spectrophotometry, Ultraviolet; Stilbenes

The amyloid-β protein precursor/presenilin 1 (AβPP/PS1) mouse model of Alzheimer's disease (AD) has provided robust neuropathological hallmarks of familial AD-like pattern. AD is a neurodegenerative process that causes severe cognitive impairment; it is characterized by the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau forms and by oxidative and inflammatory processes in brain. Currently, efforts are made to understand biochemical pathways because there is no effective therapy for AD. Resveratrol is a polyphenol that induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of oral resveratrol administration on AβPP/PS1 mice. Long-term resveratrol treatment significantly prevented memory loss as measured by the object recognition test. Moreover, resveratrol reduced the amyloid burden and increased mitochondrial complex IV protein levels in mouse brain. These protective effects of resveratrol were mainly mediated by increased activation of Sirtuin 1 and AMPK pathways in mice. However, an increase has been observed in IL1β and TNF gene expression, indicating that resveratrol promoted changes in inflammatory processes, although no changes were detected in other key actors of the oxidative stress pathway. Taken together, our findings suggest that resveratrol is able to reduce the harmful process that occurs in AβPP/PS1 mouse hippocampus, preventing memory loss.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Disease Models, Animal; Male; Memory Disorders; Memory, Short-Term; Mice, Transgenic; Neuroprotective Agents; Plaque, Amyloid; Presenilin-1; Recognition, Psychology; Resveratrol; Stilbenes

Transcranial focused ultrasound (FUS) can cause temporary, localized increases in blood-brain barrier (BBB) permeability for effective drug delivery to the brain. In pre-clinical models of Alzheimer's disease, FUS has successfully been used to deliver therapeutic agents and endogenous therapeutic molecules to the brain leading to plaque reduction and improved behavior. However, prior to moving to clinic, questions regarding how the compromised vasculature in Alzheimer's disease responds to FUS need to be addressed. Here, we used two-photon microscopy to study changes in FUS-mediated BBB permeability in transgenic (TgCRND8) mice and their non-transgenic littermates. A custom-built ultrasound transducer was attached to the skull, covering a cranial window. Methoxy-X04 was used to visualize amyloid deposits in vivo. Fluorescent intravascular dyes were used to identify leakage from the vasculature after the application of FUS. Dye leakage occurred in both transgenic and non-transgenic mice at similar acoustic pressures but exhibited different leakage kinetics. Calculation of the permeability constant demonstrated that the vasculature in the transgenic mice was much less permeable after FUS than the non-transgenic littermates. Further analysis demonstrated that the change in vessel diameter following FUS was lessened in amyloid coated vessels. These data suggest that changes in vessel diameter may be directly related to permeability and the presence of amyloid plaque may reduce the permeability of a vessel after FUS. This study indicates that the FUS parameters used for the delivery of therapeutic agents to the brain may need to be adjusted for application in Alzheimer's disease.

Topics: Alkenes; Alzheimer Disease; Animals; Benzene Derivatives; Blood-Brain Barrier; Brain; Cerebral Amyloid Angiopathy; Drug Delivery Systems; Female; Male; Mice; Mice, Transgenic; Microscopy, Fluorescence, Multiphoton; Permeability; Plaque, Amyloid; Stilbenes; Ultrasonics

Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ) and loss of neurons. Recently, a growing body of evidences have indicated that as a herbal compound naturally derived from grapes, resveratrol modulates the pathophysiology of AD, however, with a largely unclear mechanism. Therefore, we aimed to investigate the protection of resveratrol against the neurotoxicity of β-amyloid peptide 25-35 (Aβ(25-35)) and further explore its underlying mechanism in the present study. PC12 cells were injuried by Aβ(25-35), and resveratrol at different concentrations was added into the culture medium. We observed that resveratrol increased cell viability through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) colorimetric assays. Flow cytometry indicated the reduction of cell apoptosis by resveratrol. Moreover, resveratrol also stabilized the intercellular Ca(2+) homeostasis and attenuated Aβ(25-35) neurotoxicity. Additionally, Aβ(25-35)-suppressed silent information regulator 1 (SIRT1) activity was significantly reversed by resveratrol, resulting in the downregulation of Rho-associated kinase 1 (ROCK1). Our results clearly revealed that resveratrol significantly protected PC12 cells and inhibited the β-amyloid-induced cell apoptosis through the upregulation of SIRT1. Moreover, as a downstream signal molecule, ROCK1 was negatively regulated by SIRT1. Taken together, our study demonstrated that SIRT1-ROCK1 pathway played a critical role in the pathomechanism of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Apoptosis; Calcium; Cell Survival; Flow Cytometry; Gene Expression Regulation; Homeostasis; L-Lactate Dehydrogenase; Neurodegenerative Diseases; Neurons; PC12 Cells; Peptide Fragments; Rats; Resveratrol; rho-Associated Kinases; Signal Transduction; Sirtuin 1; Stilbenes; Tetrazolium Salts; Thiazoles

Alzheimer's disease drug discovery regarding exploration into the molecules and processes has focused on the intrinsic causes of the brain disorder correlated with the accumulation of amyloid-β. An anti-amyloidogenic bis-styrylbenzene derivative, KMS80013, showed excellent oral bioavailability (F=46.2%), facilitated brain penetration (26%, iv) in mouse and target specific in vivo efficacy in acute AD mouse model attenuating the cognitive deficiency in Y-maze test. Acute toxicity (LD50 >2000 mg/kg) and hERG channel inhibition (14% at 10 μM) results indicated safety of KMS80013.

Topics: Administration, Oral; Alzheimer Disease; Aniline Compounds; Animals; Benzene Derivatives; Brain; Disease Models, Animal; Ether-A-Go-Go Potassium Channels; Half-Life; Male; Mice; Mice, Inbred ICR; Stilbenes

A series of multitarget-directed resveratrol derivatives was designed and synthesized for the treatment of Alzheimer's disease (AD). In vitro studies indicated that most of the target compounds exhibit significant inhibition of self-induced β-amyloid (Aβ) aggregation and Cu(II)-induced Aβ1-42 aggregation and acted as potential antioxidants and biometal chelators. In particular, compounds 5d and 10d are potential lead compounds for AD therapy (5d, IC50 = 7.56 μM and 10d, IC50 = 6.51 μM for self-induced Aβ aggregation; the oxygen radical absorbance capacity assay using fluorescein (ORAC-FL) values are 4.72 and 4.70, respectively). Moreover, these compounds are capable of disassembling the highly structured Aβ fibrils generated by self- and Cu(II)-induced Aβ aggregation. Furthermore, 5d crossed the blood-brain barrier (BBB) in vitro and did not exhibit any acute toxicity in mice at doses of up to 2000 mg/kg. Taken together, the data indicate that 5d is a very promising lead compound for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Cholinesterase Inhibitors; Clioquinol; Drug Design; Humans; Mice; Monoamine Oxidase Inhibitors; Peptide Fragments; Resveratrol; Stilbenes

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. There is a consensus that Aβ is a pathologic agent and that its toxic effects, which are at present incompletely understood, may occur through several potential mechanisms. Polyphenols are known to have wide-ranging properties with regard to health and for helping to prevent various diseases like neurodegenerative disorders. Thus inhibiting the formation of toxic Aβ assemblies is a reasonable hypothesis to prevent and perhaps treat AD METHODS: Solution NMR and molecular modeling were used to obtain more information about the interaction between the Aβ1-40 and the polyphenol ε-viniferin glucoside (EVG) and particularly the Aβ residues involved in the complex.. The study demonstrates the formation of a complex between two EVG molecules and Aβ1-40 in peptide characteristic regions that could be in agreement with the inhibition of aggregation. Indeed, in previous studies, we reported that EVG strongly inhibited in vitro the fibril formation of the full length peptides Aβ1-40 and Aβ1-42, and had a strong protective effect against PC12 cell death induced by these peptides.. For the full length peptide Aβ1-40, the binding sites observed could explain the EVG inhibitory effect on fibrillization and thus prevent amyloidogenic neurotoxicity.. Even though this interaction might be important at the biological level to explain the protective effect of polyphenols in neurodegenerative diseases, caution is required when extrapolating this in vitro model to human physiology.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzofurans; Binding Sites; Cell Line, Tumor; Glucosides; Magnetic Resonance Spectroscopy; Models, Molecular; PC12 Cells; Peptide Fragments; Polyphenols; Protein Conformation; Rats; Stilbenes

An automated synthesis procedure of [(18)F]Florbetaben ([(18)F]BAY94-9172), a radiolabeled imaging agent in phase III study for in vivo mapping of fibrillar amyloid β (Aβ) with PET, was developed using the commercial PET-MF-2V-IT-1 synthesizer. The automated radiosynthesis was carried out via a one-step nucleophilic fluorination of methanesulfonic acid 2-[2-(2-{4-[2-(4-methylamino-phenyl)-vinyl]-phenoxy}-ethoxy)-ethoxy]-ethyl ester, as a new precursor, and separation with semi-preparative high performance liquid chromatography (HPLC). The total synthesis time amounted to 50 min with 20-25% yield (uncorrected for decay) and radiochemical purities of more than 95% in all runs. The described automated radiosynthesis allows the production of [(18)F]Florbetaben using a commercial radiosynthesis module and enables clinical trials of this compound.

Topics: Alzheimer Disease; Aniline Compounds; Automation; Chromatography, High Pressure Liquid; Fluorine Radioisotopes; Humans; Quality Control; Radionuclide Imaging; Stilbenes

Florbetaben is a β-amyloid-targeted PET tracer with significant potential for augmenting the toolbox in the clinical diagnosis of Alzheimer's disease (AD). In dementia imaging, shortening of scan duration may simplify future clinical use. The aim of this retrospective study was to investigate the effect of scan duration on diagnostic accuracy.. PET scans obtained from 25 AD patients and 25 healthy volunteers (HVs) were analysed. In each subject, scans of three different durations (5, 10 and 20 min; all starting 90 min after injection) were obtained, randomized, and visually assessed by three experts blinded to the subject's identity and group affiliation. Presence/absence of β-amyloid and diagnostic confidence (0-100 %) were scored, and 10 % of the scans were re-read. Further, randomly selected datasets of ten AD patients and ten HVs were quantified using an established VOI-based approach and using a voxel-based approach.. The sensitivity and specificity of the blinded read were 80 % and 96 %, respectively, for all scan durations. Diagnostic confidence was high (97 ± 6 %, 97 ± 6 % and 95 ± 8 % for the 20-min, 10-min and 5-min scans, respectively; n.s.), as was interreader agreement (kappa(20 min) = 0.94, kappa(10 min) = 0.94, kappa(5 min) = 0.89; n.s.). Intrareader agreement was highest for the 20-min scan (kappa = 1.00) and lower for the 10-min scan (kappa = 0.71) and 5-min scan (kappa = 0.80; p = 0.002 and 0.003 vs. the 20-min scan). For all scan durations, composite SUVRs (Cohen's d effect size 4.5, 3.9 and 4.8 for the 5-min, 10-min and 20-min scans; p < 0.0001 each) and individual brain volumes affected by β-amyloid (Cohen's d effect size 1.6, 1.8 and 2.0 for the 5-min, 10-min and 20-min scans; p < 0.005 each) were significantly higher in AD patients than in HVs.. Reduction in scan duration did not relevantly affect the accuracy of florbetaben PET scans in discriminating between AD patients and HVs. Thus, a reduction in scan duration seems conceivable for the future clinical use of florbetaben.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Brain Mapping; Case-Control Studies; Diagnostic Imaging; Female; Humans; Male; Middle Aged; Models, Statistical; Observer Variation; Positron-Emission Tomography; Random Allocation; Reproducibility of Results; Retrospective Studies; Sensitivity and Specificity; Stilbenes; Time Factors

Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.

Topics: Aging; Alzheimer Disease; Animals; Biomarkers; Blotting, Western; Caloric Restriction; Cognition; Dietary Supplements; Disease Models, Animal; Enzyme Inhibitors; Immunohistochemistry; Longevity; Mice; Resveratrol; Ribonucleotide Reductases; Stilbenes

To investigate the mRNA and protein alterations of α-synuclein in the brain of Alzheimer's disease-like mouse model at the different ages, and to evaluate the effects of 2,3,5,4'-tetrahydroxy stilbene-2-O-β-D-glucoside (TSG) on α-synuclein expression.. TSG (120 or 240 μmol kg(-1)d(-1)) was intragastrically administered to APPV717I transgenic (Tg) mice at 4- or 10-month-old for 6 months.. mRNA expression of α-synuclein increased in hippocampus in 4 month to 16 month old Tg mice compared with age-matched control. α-synuclein protein expression in hippocampus also increased in 4 month to 16 month old Tg mice significantly. Significant down-regulation of α-synuclein mRNA and protein expression in hippocampus was found after treatment of TSG for 6 months in both 10- and 16-month-old Tg mice. Production of dimer and tetramer of α-synuclein protein in Tg mice was inhibited after treatment with TSG.. The expression and aggregation of α-synuclein was age-dependently increased in Tg mice. TSG not only prevents over-expression of α-synuclein at an early stage, but also reverses the increased expression of α-synuclein and inhibits the aggregation at the late stage of Tg mice. TSG may have potential to the prevention and treatment of Alzheimer's diseases.

Topics: Aging; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Blotting, Western; Brain Chemistry; Data Interpretation, Statistical; DNA, Complementary; Glucosides; Hippocampus; Humans; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microarray Analysis; Nootropic Agents; Real-Time Polymerase Chain Reaction; RNA, Messenger; Stilbenes

Recent studies have implicated resveratrol and pterostilbene, a resveratrol derivative, in the protection against age-related diseases including Alzheimer's disease (AD). However, the mechanism for the favorable effects of resveratrol in the brain remains unclear and information about direct cross-comparisons between these analogs is rare. As such, the purpose of this study was to compare the effectiveness of diet-achievable supplementation of resveratrol to that of pterostilbene at improving functional deficits and AD pathology in the SAMP8 mouse, a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD. Furthermore we sought to determine the mechanism of action responsible for functional improvements observed by studying cellular stress, inflammation, and pathology markers known to be altered in AD. Two months of pterostilbene diet but not resveratrol significantly improved radial arm water maze function in SAMP8 compared with control-fed animals. Neither resveratrol nor pterostilbene increased sirtuin 1 (SIRT1) expression or downstream markers of sirtuin 1 activation. Importantly, markers of cellular stress, inflammation, and AD pathology were positively modulated by pterostilbene but not resveratrol and were associated with upregulation of peroxisome proliferator-activated receptor (PPAR) alpha expression. Taken together our findings indicate that at equivalent and diet-achievable doses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol, likely driven by increased peroxisome proliferator-activated receptor alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in pterostilbene.

Topics: Aging; Alzheimer Disease; Analysis of Variance; Animals; Biological Availability; Brain; Dietary Supplements; Disease Models, Animal; Female; Gas Chromatography-Mass Spectrometry; Gene Expression Regulation; Male; MAP Kinase Kinase 4; Maze Learning; Mice; Neurotransmitter Agents; NF-kappaB-Inducing Kinase; Phosphorylation; PPAR alpha; Protein Serine-Threonine Kinases; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; tau Proteins

Activation of microglia, the resident macrophages of the brain, around the amyloid plaques is a key hallmark of Alzheimer's disease (AD). Recent evidence in mouse models indicates that microglia are required for the neurodegenerative process of AD. Amyloid-β (Aβ) peptides, the core components of the amyloid plaques, can trigger microglial activation by interacting with several Toll-like receptors (TLRs), including TLR4. In this study, we show that resveratrol, a natural polyphenol associated with anti-inflammatory effects and currently in clinical trials for AD, prevented the activation of murine RAW 264.7 macrophages and microglial BV-2 cells treated with the TLR4 ligand, lipopolysaccharide (LPS). Resveratrol preferentially inhibited nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation upon LPS stimulation by interfering with IKK and IκB phosphorylation, an effect that potently reduced the transcriptional stimulation of several NF-κB target genes, including tumor necrosis factor-α and interleukin-6. Consequently, downstream phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3 upon LPS stimulation was also inhibited by resveratrol. We found that resveratrol acted upstream in the activation cascade by interfering with TLR4 oligomerization upon receptor stimulation. Resveratrol treatment also prevented the pro-inflammatory effect of fibrillar Aβ on macrophages by potently inhibiting the effect of Aβ on IκB phosphorylation, activation of STAT1 and STAT3, and on tumor necrosis factor-α and interleukin-6 secretion. Importantly, orally administered resveratrol in a mouse model of cerebral amyloid deposition lowered microglial activation associated with cortical amyloid plaque formation. Together this work provides strong evidence that resveratrol has in vitro and in vivo anti-inflammatory effects against Aβ-triggered microglial activation. Further studies in cell culture systems showed that resveratrol acted via a mechanism involving the TLR4/NF-κB/STAT signaling cascade.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Transformed; Cytokines; Disease Models, Animal; Drug Interactions; Humans; I-kappa B Proteins; Inflammation Mediators; Lipopolysaccharides; Male; Mice; Mice, Transgenic; Microglia; NF-KappaB Inhibitor alpha; Presenilin-1; Resveratrol; Signal Transduction; Statistics, Nonparametric; Stilbenes; Time Factors; Toll-Like Receptors; Tumor Necrosis Factor-alpha

Early diagnosis of Alzheimer's disease (AD) may be corroborated by imaging of beta-amyloid plaques using positron emission tomography (PET). Here, we performed an add-on questionnaire study to evaluate the relevance of florbetaben imaging (BAY 949172) in diagnosis and consecutive management of probable AD patients.. AD patients with a clinical diagnosis in accordance with the NINCDS-ADRDA criteria or controls were imaged using florbetaben. Referring physicians were asked on a voluntary basis about their confidence in initial diagnosis, significance of PET imaging results, and their anticipated consequences for future patient care.. 121 questionnaires for probable AD patients and 80 questionnaires for controls were evaluated. In 18% of patients who had initially received the diagnosis of probable AD, PET scans were rated negative, whereas in controls 18% of scans were positive. An increase in confidence in the initial diagnosis was frequently reported (80%). Imaging results had a significant impact on the intended patient care, as judged by the referring physicians; this was most prominent in those patients with a contradicting scan and/or a low confidence in the initial diagnosis.. Florbetaben amyloid imaging increases the overall confidence in diagnosis of AD and may frequently influence clinical decisions and patient management.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Decision Making; Early Diagnosis; Female; Humans; Male; Patient Care Planning; Positron-Emission Tomography; Practice Patterns, Physicians'; Radiopharmaceuticals; Stilbenes

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

Transthyretin (TTR) protects against A-Beta toxicity by binding the peptide thus inhibiting its aggregation. Previous work showed different TTR mutations interact differently with A-Beta, with increasing affinities correlating with decreasing amyloidogenecity of the TTR mutant; this did not impact on the levels of inhibition of A-Beta aggregation, as assessed by transmission electron microscopy. Our work aimed at probing differences in binding to A-Beta by WT, T119M and L55P TTR using quantitative assays, and at identifying factors affecting this interaction. We addressed the impact of such factors in TTR ability to degrade A-Beta. Using a dot blot approach with the anti-oligomeric antibody A11, we showed that A-Beta formed oligomers transiently, indicating aggregation and fibril formation, whereas in the presence of WT and T119M TTR the oligomers persisted longer, indicative that these variants avoided further aggregation into fibrils. In contrast, L55PTTR was not able to inhibit oligomerization or to prevent evolution to aggregates and fibrils. Furthermore, apoptosis assessment showed WT and T119M TTR were able to protect against A-Beta toxicity. Because the amyloidogenic potential of TTR is inversely correlated with its stability, the use of drugs able to stabilize TTR tetrameric fold could result in increased TTR/A-Beta binding. Here we showed that iododiflunisal, 3-dinitrophenol, resveratrol, [2-(3,5-dichlorophenyl)amino] (DCPA) and [4-(3,5-difluorophenyl)] (DFPB) were able to increase TTR binding to A-Beta; however only DCPA and DFPB improved TTR proteolytic activity. Thyroxine, a TTR ligand, did not influence TTR/A-Beta interaction and A-Beta degradation by TTR, whereas RBP, another TTR ligand, not only obstructed the interaction but also inhibited TTR proteolytic activity. Our results showed differences between WT and T119M TTR, and L55PTTR mutant regarding their interaction with A-Beta and prompt the stability of TTR as a key factor in this interaction, which may be relevant in AD pathogenesis and for the design of therapeutic TTR-based therapies.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Cell Line, Tumor; Diflunisal; Dinitrophenols; Humans; Mutation; Phthalic Acids; Prealbumin; Protein Binding; Resveratrol; Stilbenes

The progression of Alzheimer's disease (AD) is accompanied by disturbances of the endosome/lysosome (EL) system and there is accumulation of peptides of the AD-associated amyloid beta (Abeta) type in EL vesicles of affected neurons. EL modulating agents partially ameliorate the Abeta-mediated cell abnormalities. However, no extensive studies on the potential pharmaceutical applications of combinations of such agents and their synergistic effects have been performed. This study shows the beneficial anti-amyloid effects of several combinations of lysosomal modulators and other pharmacological and new nanobiotechnological agents. Some agents potentiated each other's action and some of them facilitated the anti-amyloid actions of memantine, a modifier of Ca2+-permeable channels involved in AD and one of the few drugs used for treatment of AD. Another compound used in nanobiotechnology ameliorated as a nanocarrier the beneficial effects of some of these potential pharmaceutical agents. They may be considered as additional drugs to improve the efficacy of the therapeutic approaches for AD and related neurodegenerative disorders.

Topics: Acetylcarnitine; Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Cell Survival; Drug Carriers; Endosomes; Humans; Kaempferols; Lactic Acid; Lysosomes; Memantine; Mifepristone; Nanoparticles; Neuroprotective Agents; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Resveratrol; Stilbenes

A series of novel resveratrol derivatives were designed, synthesised and evaluated as potential therapeutic agents for the treatment of Alzheimer's disease. Among these compounds, compound 7l, (E)-5-(4-(isopropylamino)styryl)benzene-1,3-diol, exhibited potent ß-amyloid aggregation inhibition activity, which was confirmed by a ThT fluorescence assay (71.65% at 20 μM) and transmission electron microscopy (TEM). Compound 7l also exhibited good antioxidant activity (4.12 Trolox equivalents in an oxygen radical absorbance capacity assay and a 37% reduction in reactive oxygen species in cells at 10 μM). The cytotoxicity analysis of compounds 7f, 7i, 7j and 7l indicated that these compounds have lower toxicities than resveratrol at 60 μM.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Humans; Molecular Structure; Neuroprotective Agents; Peptide Fragments; Reactive Oxygen Species; Resveratrol; Stilbenes; Structure-Activity Relationship

The aim of this study was to evaluate the protective effects of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), an active component extracted from Polygonum multiflorum, on learning/memory deficits in Alzheimer's disease (AD). We randomly divided 24 male Sprague-Dawley rats among 4 groups: (i) the sham-operated group (control); (ii) sham-operated group also treated with TSG (sham+TSG); (iii) beta amyloid treated group (Aβ); and (iv) Aβ treatment group also treated with TSG (Aβ+TSG). Rats in the Aβ and Aβ+TSG groups were treated with Aβ₁₋₄₂ intracerebroventricularly, whereas the control and sham+TSG groups were given phosphate-buffered saline. Rats in the sham+TSG and Aβ+TSG groups were then treated intragastrically with TSG (50 mg·(kg body mass)⁻¹·day⁻¹) for 4 weeks, and rats in the Aβ and control groups were treated with saline. The results from Morris water maze tests, electron microscopy, real-time polymerase chain reaction, and Western blotting demonstrated that Aβ₁₋₄₂ induced impairment in learning and memory, degeneration in synaptic structures, and downregulation of Src and NR2B at the gene and protein level, respectively. These alterations were reversed by the administration of TSG, suggesting that TSG exerts anti-AD properties by protecting synaptic structure and function. TSG-induced upregulation of Src and NR2B may be responsible for this process.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Glucosides; Hippocampus; Learning Disabilities; Male; Memory Disorders; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Nootropic Agents; Peptide Fragments; Proto-Oncogene Proteins pp60(c-src); Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Stilbenes; Synaptic Membranes; Up-Regulation

Abnormal β-amyloid peptide accumulation and aggregation is considered to be responsible for the formation and cerebral deposition of senile plaques in the brains of patients with Alzheimer's disease (AD). Inhibition of the formation of β-amyloid (Aβ) fibrils would be an attractive therapeutic target for the treatment of AD. Resveratrol and its derivatives exhibit a broad range of pharmacological properties such as protection against cardiovascular diseases and cancers, as well as promoting antiaging effects. We reported previously that ε-viniferin glucoside (VG), a resveratrol-derived dimer, strongly inhibits Aβ (25-35) fibril formation in vitro. In this study, we investigated the effects of VG on the aggregation of the full-length peptides (Aβ (1-40) and Aβ (1-42)) and on the β-amyloid-induced toxicity in PC12 cells. VG inhibited Aβ cytotoxicity and the non-covalent complex between VG and Aβ was observed by electrospray ionization mass spectrometry.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzofurans; Humans; PC12 Cells; Rats; Spectrometry, Mass, Electrospray Ionization; Stilbenes; Vitis

Aside from being an integral protein involved in the synthesis and hydrolysis of ATP, Ecto-F1-ATPase plays a role in cholesterol homeostasis. We demonstrated the presence of autoantibodies to ecto-F1-ATPase (ASabs) in sera and cerebrospinal fluids from patients with Alzheimer's disease (AD). Herein we show that ASabs, unlike irrelevant antibodies, can increase cellular uptake of HDL, a risk factor for the development of AD, via a mechanism involving the prototypical function of ecto-F1-ATPase: the generation of ADP due to the hydrolysis of ATP. Piceatannol, a specific inhibitor ecto-F1-ATPase, completely hindered these effects. We hypothesize that ASabs could exert a pathogenetic role in AD.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Aged; Aged, 80 and over; Alzheimer Disease; Antibody Specificity; Apoptosis; Autoantibodies; Cell Line; Cholesterol, HDL; Enzyme Inhibitors; Extracellular Space; Female; Fluorescent Dyes; Humans; Male; Middle Aged; Proton-Translocating ATPases; Stilbenes

It has been recently suggested that resveratrol can be effective in slowing down Alzheimer's disease (AD) development. As reported in many biochemical studies, resveratrol seems to exert its neuro-protective role through inhibition of β-amyloid aggregation (Aβ), by scavenging oxidants and exerting anti-inflammatory activities. In this paper, we demonstrate that resveratrol is cytoprotective in human neuroblastoma cells exposed to Aβ and or to Aβ-metal complex. Our findings suggest that resveratrol acts not through anti-aggregative pathways but mainly via its scavenging properties.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Cell Line, Tumor; Coordination Complexes; Humans; Neuroblastoma; Resveratrol; Signal Transduction; Stilbenes

Amyloid imaging with (18)F-labeled radiotracers will allow widespread use, facilitating research, diagnosis, and therapeutic development for Alzheimer disease. The purpose of the study program was to compare cortical amyloid deposition using (18)F-florbetaben and PET in controls and subjects with mild cognitive impairment (MCI), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies (DLB), vascular dementia (VaD), Parkinson disease (PD), and Alzheimer disease (AD).. One hundred nine subjects in 3 clinical studies at Austin Health were reviewed: 32 controls, 20 subjects with MCI, and 30 patients with AD, 11 with FTLD, 7 with DLB, 5 with PD, and 4 with VaD underwent PET after intravenous injection of 300 MBq of (18)F-florbetaben. Standardized uptake value ratios (SUVR) using the cerebellar cortex as a reference region were calculated between 90 and 110 min after injection.. When compared with the other groups, AD patients demonstrated significantly higher SUVRs (P < 0.0001) in neocortical areas. Most AD patients (96%) and 60% of MCI subjects showed diffuse cortical (18)F-florbetaben retention. In contrast, only 9% of FTLD, 25% of VaD, 29% of DLB, and no PD patients and 16% of controls showed cortical binding. Although there was a correlation between Mini Mental State Examination and β-amyloid burden in the MCI group, no correlation was observed in controls, FTLD or AD.. (18)F-florbetaben had high sensitivity for AD, clearly distinguished patients with FTLD from AD, and provided results comparable to those reported with (11)C-Pittsburgh Compound B in a variety of neurodegenerative diseases.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Case-Control Studies; Cerebellum; Dementia; Female; Fluorine Radioisotopes; Frontotemporal Dementia; Humans; Image Processing, Computer-Assisted; Lewy Bodies; Male; Middle Aged; Neurodegenerative Diseases; Positron-Emission Tomography; Radioisotopes; Stilbenes; Treatment Outcome

Amyloid-β (Aβ) peptides and their metal-associated aggregated states have been implicated in the pathogenesis of Alzheimer's disease (AD). Although the etiology of AD remains uncertain, understanding the role of metal-Aβ species could provide insights into the onset and development of the disease. To unravel this, bifunctional small molecules that can specifically target and modulate metal-Aβ species have been developed, which could serve as suitable chemical tools for investigating metal-Aβ-associated events in AD. Through a rational structure-based design principle involving the incorporation of a metal binding site into the structure of an Aβ interacting molecule, we devised stilbene derivatives (L1-a and L1-b) and demonstrated their reactivity toward metal-Aβ species. In particular, the dual functions of compounds with different structural features (e.g., with or without a dimethylamino group) were explored by UV-vis, X-ray crystallography, high-resolution 2D NMR, and docking studies. Enhanced bifunctionality of compounds provided greater effects on metal-induced Aβ aggregation and neurotoxicity in vitro and in living cells. Mechanistic investigations of the reaction of L1-a and L1-b with Zn(2+)-Aβ species by UV-vis and 2D NMR suggest that metal chelation with ligand and/or metal-ligand interaction with the Aβ peptide may be driving factors for the observed modulation of metal-Aβ aggregation pathways. Overall, the studies presented herein demonstrate the importance of a structure-interaction-reactivity relationship for designing small molecules to target metal-Aβ species allowing for the modulation of metal-induced Aβ reactivity and neurotoxicity.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Cell Survival; Chelating Agents; Copper; Crystallography, X-Ray; Drug Design; Humans; Iron; Ligands; Magnetic Resonance Spectroscopy; Microscopy, Electron, Transmission; Models, Molecular; Molecular Probes; Protein Conformation; Stilbenes; Structure-Activity Relationship; Zinc

Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Fluorine Radioisotopes; Humans; Plaque, Amyloid; Positron-Emission Tomography; Pyridines; Stilbenes; Styrenes; Tissue Distribution

Alzheimer disease is an age-related neurodegenerative disorder characterized by amyloid-beta (Abeta) peptide deposition into cerebral amyloid plaques. The natural polyphenol resveratrol promotes anti-aging pathways via the activation of several metabolic sensors, including the AMP-activated protein kinase (AMPK). Resveratrol also lowers Abeta levels in cell lines; however, the underlying mechanism responsible for this effect is largely unknown. Moreover, the bioavailability of resveratrol in the brain remains uncertain. Here we show that AMPK signaling controls Abeta metabolism and mediates the anti-amyloidogenic effect of resveratrol in non-neuronal and neuronal cells, including in mouse primary neurons. Resveratrol increased cytosolic calcium levels and promoted AMPK activation by the calcium/calmodulin-dependent protein kinase kinase-beta. Direct pharmacological and genetic activation of AMPK lowered extracellular Abeta accumulation, whereas AMPK inhibition reduced the effect of resveratrol on Abeta levels. Furthermore, resveratrol inhibited the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of Abeta. Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral Abeta levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against Alzheimer disease.

Topics: Alzheimer Disease; AMP-Activated Protein Kinases; Amyloid beta-Peptides; Animals; Autophagy; Calcium; Cytosol; Enzyme Inhibitors; Humans; Lysosomes; Male; Mice; Mice, Transgenic; Neurons; Resveratrol; Signal Transduction; Stilbenes

We report on a series of hybrid compounds structurally derived from donepezil and AP2238. This study was aimed at improving the activities of the reference compounds, donepezil and AP2238, and at broadening the range of activities of new derivatives as, due to the multifactorial nature of AD, molecules that modulate the activity of a single protein target are unable to significantly modify the progression of the disease. In particular, the indanone core from donepezil was linked to the phenyl-N-methylbenzylamino moiety from AP2238, through a double bond that was kept to evaluate the role of a lower flexibility in the biological activities. Moreover, SAR studies were performed to evaluate the role of different substituents in position 5 or 6 of the indanone ring in the interaction with the PAS, introducing also alkyl chains of different lengths carrying different amines at one end. Derivatives 21 and 22 proved to be the most active within the series and their potencies against AChE were in the same order of magnitude of the reference compounds. Compounds 15, 21-22, with a 5-carbon alkyl chain bearing an amino moiety at one end, better contacting the PAS, remarkably improved the inhibition of AChE-induced Abeta aggregation with respect to the reference compounds. They also showed activity against self-aggregation of Abeta(42) peptide, the most amyloidogenic form of amyloid produced in AD brains, while the reference compounds resulted completely ineffective.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antineoplastic Combined Chemotherapy Protocols; Benzylamines; Binding Sites; Bleomycin; Cholinesterase Inhibitors; Computer Simulation; Coumarins; Donepezil; Humans; Indans; Lomustine; Methotrexate; Peptide Fragments; Piperidines; Recombinant Proteins; Stilbenes; Structure-Activity Relationship; Tetrahydronaphthalenes

A bis(thiosemicarbazonato)copper(ii) complex with an appended stilbene functional group binds to amyloid-beta plaques that are associated with Alzheimer's disease. The complex has the potential to be of use as a copper-64 radiopharmaceutical to assist in the diagnosis of Alzheimer's disease by positron emission tomography.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Copper Radioisotopes; Humans; Mice; Organometallic Compounds; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes; Thiosemicarbazones

Fluorescence probes that can detect Aβ (β-amyloid peptide) plaque are important tools for diagnosis of Alzheimer's disease (AD), and 4-N-methylamino-4'-hydroxystilbene (SB-13) is one of the promising candidate molecules. We report here the synthesis of SB-13 derivatives that consist of various electron donating/withdrawing moieties and distinct size of N-substituents. The synthesized compounds were screened for detection of Aβ40 fibrils in vitro. Four compounds exhibited more than sixfold intensity increase, and they were further analyzed for detail bindings and Aβ plaque imaging. Among these molecules, compound 42 meets two critical requirements for imaging agent; high fluorescence responsiveness and strong binding affinity. This compound showed more than 25-fold increase with the dissociation constant of 1.13±0.37μM. In AD mouse brain tissue, 42 selectively stained Aβ plaque, more specifically peripheral regions of Aβ plaque. This finding demonstrated its potential use as brain-imaging agents for AD studies.

Topics: Alzheimer Disease; Animals; Brain; Fluorescent Dyes; Mice; Plaque, Amyloid; Positron-Emission Tomography; Stilbenes; Tomography, Emission-Computed, Single-Photon

Starting from bisphenolic bis-styrylbenzene DF-9 (4), β-amyloid (Aβ) binding affinity and specificity for phenolic bis-styrylbenzenes, monostyrylbenzenes, and alkyne controls were determined by fluorescence titration with β-amyloid peptide Aβ(1-40) and a fluorescence assay using APP/PS1 transgenic mouse brain sections. Bis-styrylbenzene SAR is derived largely from work on symmetrical compounds. This study is the first to describe Aβ binding data for bis-styrylbenzenes unsymmetrical in the outer rings. With one exception, binding affinity and specificity were decreased by adding and/or changing the substitution pattern of phenol functional groups, changing the orientation about the central phenyl ring, replacing the alkene with alkyne bonds, or eliminating the central phenyl ring. The only compound with an Aβ binding affinity and specificity comparable to 4 was its 3-hydroxy regioisomer 8. Like 4, 8 crossed the blood-brain barrier and bound to Aβ plaques in vivo. By use of a DPPH assay, phenol functional groups with para orientations seem to be a necessary, but insufficient, criterion for good free radical scavenging properties in these compounds.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Brain; Drug Design; Free Radical Scavengers; Humans; In Vitro Techniques; Ligands; Mice; Mice, Transgenic; Phenols; Plaque, Amyloid; Protein Binding; Stereoisomerism; Stilbenes

This study investigated a methanol extract from the leaf and stem of Vitis amurensis (Vitaceae) for possible neuroprotective effects on neurotoxicity induced by amyloid β protein (Aβ) (25-35) in cultured rat cortical neurons and also for antidementia activity in mice. Exposure of cultured cortical neurons to 10 μM Aβ (25-35) for 36 h induced neuronal apoptotic death. At concentrations of 1-10 μg/mL, V. amurensis inhibited neuronal death, the elevation of intracellular calcium ([Ca(2+)](i)) and the generation of reactive oxygen species (ROS), all of which were induced by Aβ (25-35) in primary cultures of rat cortical neurons. Memory loss induced by intracerebroventricular injection of ICR mice with 16 nmol Aβ (25-35) was inhibited by chronic treatment with V. amurensis extract (50 and 100 mg/kg, p.o. for 7 days), as measured by a passive avoidance test. Amurensin G, r-2-viniferin and trans-ɛ-viniferin isolated from V. amurensis also inhibited neuronal death, the elevation of [Ca(2+)](i) and the generation of ROS induced by Aβ (25-35) in cultured rat cortical neurons. These results suggest that the neuroprotective effect of V. amurensis may be partially attributable to these compounds. These results suggest that the antidementia effect of V. amurensis is due to its neuroprotective effect against Aβ (25-35)-induced neurotoxicity and that the leaf and stem of V. amurensis have possible therapeutic roles for preventing the progression of Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Benzofurans; Cells, Cultured; Cerebral Cortex; Dibenzocycloheptenes; Dose-Response Relationship, Drug; Embryo, Mammalian; GPI-Linked Proteins; Male; Memory Disorders; Mice; Mice, Inbred ICR; Neurons; Neuroprotective Agents; Peptide Fragments; Phytotherapy; Plant Extracts; Plant Leaves; Plant Stems; Rats; Rats, Sprague-Dawley; Resorcinols; Stilbenes; Vitis

Resveratrol, a polyphenol found in red wine, peanuts, soy beans, and pomegranates, possesses a wide range of biological effects. Since resveratrol's properties seem ideal for treating neurodegenerative diseases, its ability to diminish amyloid plaques was tested. Mice were fed clinically feasible dosages of resveratrol for forty-five days. Neither resveratrol nor its conjugated metabolites were detectable in brain. Nevertheless, resveratrol diminished plaque formation in a region specific manner. The largest reductions in the percent area occupied by plaques were observed in medial cortex (-48%), striatum (-89%) and hypothalamus (-90%). The changes occurred without detectable activation of SIRT-1 or alterations in APP processing. However, brain glutathione declined 21% and brain cysteine increased 54%. The increased cysteine and decreased glutathione may be linked to the diminished plaque formation. This study supports the concept that onset of neurodegenerative disease may be delayed or mitigated with use of dietary chemo-preventive agents that protect against beta-amyloid plaque formation and oxidative stress.

Topics: Alzheimer Disease; Animals; Antioxidants; Ascorbic Acid; Benzothiazoles; Blotting, Western; Brain; Cerebral Ventricles; Cysteine; Dietary Supplements; Female; Glutathione; Hippocampus; Humans; Immunohistochemistry; Male; Mice; Mice, Transgenic; Plaque, Amyloid; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes; tau Proteins; Thiazoles; Transcription Factors; Tumor Suppressor Protein p53

Grapes are a valuable source of numerous phytonutrients, including the intensively studied constituent, resveratrol. A question worth addressing is the potential of dietary grape consumption to positively modulate human health. Many studies have suggested cardiovascular benefits, and some work has indicated cancer chemopreventive activity. Data are particularly compelling in the area of skin cancer prevention. With financial support provided by the California Table Grape Commission, novel and exciting preliminary data are emerging from independent research suggesting beneficial activity against other less prevalent but devastating illnesses, such as Alzheimer's disease and urinary bladder dysfunction. It is further suggested that some of the copious amounts of data obtained with resveratrol may be relevant to grape consumption, especially responses that can be mediated by low concentrations of the substance. Whether future specific health claims will be sought from or allowed by regulatory authorities is not known, but based on existing data, it is clear that grapes should be considered an integral component of fruit and vegetable enriched diets that are recommended by health authorities and widely accepted as beneficial for human health and disease prevention.

Topics: Alzheimer Disease; Animals; Anticarcinogenic Agents; Diet; Fruit; Health Promotion; Humans; Resveratrol; Stilbenes; Urinary Bladder Diseases; Vitis

Topics: Alkenes; Alzheimer Disease; Animals; Benzene Derivatives; Brain; Disease Models, Animal; Mice; Plaque, Amyloid; Stilbenes

Topics: Alkenes; Alzheimer Disease; Animals; Benzene Derivatives; Brain; Disease Models, Animal; Mice; Plaque, Amyloid; Stilbenes

Aggregation of amyloid-beta (Abeta) peptide in the brain in the form of neuritic plaques and cerebral amyloid angiopathy (CAA) is a key feature of Alzheimer's disease (AD). Microglial cells surround aggregated Abeta and are believed to play a role in AD pathogenesis. A therapy for AD that has entered clinical trials is the administration of anti-Abeta antibodies. One mechanism by which certain anti-Abeta antibodies have been proposed to exert their effects is via antibody-mediated microglial activation. Whether, when, or to what extent microglial activation occurs after systemic administration of anti-Abeta antibodies has not been fully assessed. We administered an anti-Abeta antibody (m3D6) that binds aggregated Abeta to PDAPP mice, an AD mouse model that was bred to contain fluorescent microglia. Three days after systemic administration of m3D6, there was a marked increase in both the number of microglial cells and processes per cell visualized in vivo by multiphoton microscopy. These changes required the Fc domain of m3D6 and were not observed with an antibody specific to soluble Abeta. These findings demonstrate that some effects of antibodies that recognize aggregated Abeta are rapid, involve microglia, and provide insight into the mechanism of action of a specific passive immunotherapy for AD.

Topics: Age Factors; Alkenes; Alzheimer Disease; Amyloid; Amyloid beta-Protein Precursor; Animals; Antibodies; Benzene Derivatives; Calcium-Binding Proteins; Cell Count; Cell Movement; Cerebral Amyloid Angiopathy; CX3C Chemokine Receptor 1; Disease Models, Animal; Green Fluorescent Proteins; Leukocyte Common Antigens; Mice; Mice, Transgenic; Microfilament Proteins; Microglia; Plaque, Amyloid; Receptors, Chemokine; Stilbenes

Amyloid-beta (Abeta) plaque formation is a hallmark of Alzheimer's disease (AD) and precedes the onset of dementia. Abeta imaging should allow earlier diagnosis, but clinical application is hindered by the short decay half-life of current Abeta-specific ligands. (18)F-BAY94-9172 is an Abeta ligand that, due to the half-life of (18)F, is suitable for clinical use. We thus studied the effectiveness of this ligand in identifying patients with AD.. 15 patients with mild AD, 15 healthy elderly controls, and five individuals with frontotemporal lobar degeneration (FTLD) were studied. (18)F-BAY94-9172 binding was quantified by use of the standardised uptake value ratio (SUVR), which was calculated for the neocortex by use of the cerebellum as reference region. SUVR images were visually rated as normal or AD.. (18)F-BAY94-9172 binding matched the reported post-mortem distribution of Abeta plaques. All AD patients showed widespread neocortical binding, which was greater in the precuneus/posterior cingulate and frontal cortex than in the lateral temporal and parietal cortex. There was relative sparing of sensorimotor, occipital, and medial temporal cortex. Healthy controls and FTLD patients showed only white-matter binding, although three controls and one FTLD patient had mild uptake in frontal and precuneus cortex. At 90-120 min after injection, higher neocortical SUVR was observed in AD patients (2.0 [SD 0.3]) than in healthy controls (1.3 [SD 0.2]; p<0.0001) or FTLD patients (1.2 [SD 0.2]; p=0.009). Visual interpretation was 100% sensitive and 90% specific for detection of AD.. (18)F-BAY94-9172 PET discriminates between AD and FTLD or healthy controls and might facilitate integration of Abeta imaging into clinical practice.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Dementia; Diagnosis, Differential; Female; Humans; Image Interpretation, Computer-Assisted; Isotope Labeling; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Female; Humans; Male; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes

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

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

A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.

Topics: Acetylation; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Cells, Cultured; Cyclin-Dependent Kinase 5; Disease Models, Animal; Enzyme Activation; Gene Expression Regulation; Humans; Mice; Mice, Transgenic; Mutation; Nerve Degeneration; Rats; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes; Superoxide Dismutase; Superoxide Dismutase-1; Tumor Suppressor Protein p53

Cerebral amyloid angiopathy (CAA), the deposition of cerebrovascular beta-amyloid (Abeta) in the walls of arterial vessels, has been implicated in hemorrhagic stroke and is present in most cases of Alzheimer disease. Previous studies of the progression of CAA in humans and animal models have been limited to the comparison of pathological tissue from different brains at single time points. Our objective was to visualize in real time the initiation and progression of CAA in Tg2576 mice by multiphoton microscopy through cranial windows. Affected vessels were labeled by methoxy-X04, a fluorescent dye that selectively binds cerebrovascular beta-amyloid and plaques. With serial imaging sessions spaced at weekly intervals, we were able to observe the earliest appearance of CAA in leptomeningeal arteries as multifocal deposits of band-like Abeta. Over subsequent imaging sessions, we were able to identify growth of these deposits (propagation), as well as appearance of new bands (additional initiation events). Statistical modeling of the data suggested that as the extent of CAA progressed in this vascular bed, there was increased prevalence of propagation over initiation. During the early phases of CAA development, the overall pathology burden progressed at a rate of 0.35% of total available vessel area per day (95% confidence interval, 0.3-0.4%). The consistent rate of disease progression implies that this model is amenable to investigations of therapeutic interventions.

Topics: Alkenes; Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzene Derivatives; Cerebral Amyloid Angiopathy; Craniotomy; Disease Models, Animal; Disease Progression; Fluorescent Dyes; Humans; Image Processing, Computer-Assisted; Kinetics; Meninges; Mice; Mice, Transgenic; Plaque, Amyloid; Skin Window Technique; Stilbenes

To investigate learning-memory deficit in different ages of AD-like APP transgenic mice and to observe the protective effects of 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside (TSG), which is the main component of Polygonum multiflorum, on learning-memory abilities.. PDAPPV717I transgenic (Tg) mice were randomly divided into 3 model groups (4, 10 and 16 months old mice) and TSG treated (at doses 120 and 240 micromol/kg/d) groups. TSG was administered to some Tg mice with an age range 4-10 months. In untreated 10 months old Tg mice, the TSG was administrated to those falling in the age range 10-16 months. For the control group we adopted the same age and background C57BL/6J mice. The learning-memory ability was measured by applying Morris water maze (MWM) and object recognition test (ORT).. In the 4 months old PDAPPV717I Tg mice, the learning-memory deficit was detected. The escape latency in MWM was prolonged, and the discrimination index decreased in ORT. In the 10 months old Tg mice, the learning-memory deficit was aggravated. TSG improved all spatial learning-memory impairment in MWM as well as the object recognition impairment in ORT. In the 16 months old Tg mice, the learning-memory deficit remained to exist but abated a lot. TSG showed significant improvement in learning-memory ability in both MWM and ORT.. PDAPPV717I transgenic mice with an age range 4-16 months revealed the existence of learning-memory deficit compared with the control group. Tetrahydroxystilbene glucoside not only prevents, i.e. at an early stage, the learning-memory deficit in AD-like model, but also can reverse the learning-memory deficit in the late stage of AD-like model. Thus, TSG could be considered among the future therapeutic drugs indicated for the treatment of AD.

Topics: Age Factors; Aging; Alzheimer Disease; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Disease Models, Animal; Glucosides; Learning Disabilities; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pattern Recognition, Visual; Stilbenes

To explore the effect of resveratrol on the cognition of Alzheimer's mice (AD) and its mechanism, and to assess its action on the reproduction system.. According to the results of step-down test, 84 Kunming female mice were randomly divided into 6 groups: Group A [sham operated+1% CMC-Na (0.01 mL/g)], Group B [ovariectomy+D-galactose+1% CMC-Na (0.01 mL/g)], Group C [ovariectomy+D-galactose+0.05 mg/(kg.d) Diethylstilbestrol], Group D [ovariectomy+D-galactose+15 mg/(kg.d) Res], and Group E [ovariectomy+D-galactose injected+45 mg/(kg.d) Res], and Group F [ovariectomy+D-galactose +135 mg/(kg.d) Res]. Experimental cycle was 60 days.. Resveratrol of every dosage could improve the performance records of behavior tests in AD mice,could inhibit the SOD vitality and the MDA level both in the serum and in the brain, and could suppress the acetylcholinesterase vitality and the bax expression. Resveratrol has no endometrial hyperplasia effect.. Resveratrol can improve the cognitive ability of AD mice, which may contribute to the resveratrol's antioxidation and antiapoptosis, and can modulate acetylcholinesterase. Resveratrol has no side-effect of endometrial hyperplasia on AD mice.

Topics: Alzheimer Disease; Animals; Antioxidants; Cognition; Female; Galactose; Mice; Ovariectomy; Random Allocation; Resveratrol; Stilbenes

Amyloid beta (1-42) peptide is considered responsible for the formation of senile plaques that accumulate in the brains of patients with Alzheimer's disease (AD). In the last years considerable attention has been focused on identifying natural food products, such as phytochemicals that prevent or almost retard the appearance of amyloid beta (1-42)-related neurotoxic effects. In this study, human neuroblastoma cells (IMR-32) was used as system model to evaluate the protective role of rhaponticin (3,3',5-trihydroxy-4'-methoxystilbene 3-O-d-glucoside) a stilbene glucoside extracted from rhubarb roots (Rhei rhizoma) and rhapontigenin, its aglycone metabolite, against amyloid beta (1-42)-dependent toxicity. The obtained results show that rhapontigenin maintains significant cell viability in a dose-dependent manner and it exerts a protective effect on mitochondrial functionality, as evidenced by mitochondrial oxygen consumption experiments. A similar behaviour, but to a lesser extent, has been shown by rhaponticin. The protective mechanism mediated by the two stilbenes could be related to their effect on bcl-2 gene family expression. Bax, a pro-apoptotic gene, resulted down-regulated by the treatment with rhaponticin and rhapontigenin compared with the results obtained in the presence of amyloid beta (1-42) peptide. Conversely, bcl-2, an anti-apoptotic gene, highly down-regulated by amyloid beta (1-42) treatment, resulted expressed in the presence of stilbenes similarly to that shown by control cells. The obtained results support the hypothesis that amyloid beta (1-42)-induced neurotoxicity occurs via bax over-expression, bcl-2 down-regulation, firstly indicating that rhaponticin and its aglycone moiety may alter this cell death pathway. Based on these studies, we suggest that rhaponticin and its main metabolite could be developed as agents for the management of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Humans; Mitochondria; Nerve Degeneration; Neuroprotective Agents; Oxygen Consumption; Peptide Fragments; Plant Extracts; Plaque, Amyloid; Rheum; Signal Transduction; Stilbenes

Imaging agents targeting beta-amyloid (Abeta) may be useful for diagnosis and treatment of patients with Alzheimer's disease (AD). Compounds 3e and 4e are fluorinated stilbene derivatives displaying high binding affinities for Abeta plaques in AD brain homogenates (Ki = 15 +/- 6 and 5.0 +/- 1.2 nM, respectively). In vivo biodistributions of [18F]3e and [18F]4e in normal mice exhibited excellent brain penetrations (5.55 and 9.75% dose/g at 2 min), and rapid brain washouts were observed, especially for [18F]4e (0.72% dose/g at 60 min). They also showed in vivo plaque labeling in APP/PS1 or Tg2576 transgenic mice, animal models for AD. Autoradiography of postmortem AD brain sections and AD homogenate binding studies confirmed the selective and specific binding properties to Abeta plaques. In conclusion, the preliminary results strongly suggest that these fluorinated stilbene derivatives, [18F]3e and [18F]4e, are suitable candidates as Abeta plaque imaging agents for studying patients with AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Fluorine Radioisotopes; Humans; Mice; Mice, Inbred ICR; Mice, Transgenic; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes; Structure-Activity Relationship; Tissue Distribution

Several epidemiological studies indicate that moderate consumption of wine is associated with a lower incidence of Alzheimer's disease. Wine is enriched in antioxidant compounds with potential neuroprotective activities. However, the exact molecular mechanisms involved in the beneficial effects of wine intake on the neurodegenerative process in Alzheimer's disease brain remain to be clearly defined. Here we show that resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-beta (Abeta) peptides produced from different cell lines. Resveratrol does not inhibit Abeta production, because it has no effect on the Abeta-producing enzymes beta- and gamma-secretases, but promotes instead intracellular degradation of Abeta via a mechanism that involves the proteasome. Indeed, the resveratrol-induced decrease of Abeta could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit beta5. These findings demonstrate a proteasome-dependent anti-amyloidogenic activity of resveratrol and suggest that this natural compound has a therapeutic potential in Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Catechin; Cell Line; Gene Expression Regulation; Humans; Molecular Structure; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Quercetin; Resveratrol; Stilbenes; Wine

Accumulating evidence suggests that neurodegeneration induced by pathogenic proteins depends on contributions from surrounding glia. Here we demonstrate that NF-kappaB signaling in microglia is critically involved in neuronal death induced by amyloid-beta (Abeta) peptides, which are widely presumed to cause Alzheimer disease. Constitutive inhibition of NF-kappaB signaling in microglia by expression of the nondegradable IkappaBalpha superrepressor blocked neurotoxicity, indicating a pivotal role for microglial NF-kappaB signaling in mediating Abeta toxicity. Stimulation of microglia with Abeta increased acetylation of RelA/p65 at lysine 310, which regulates the NF-kappaB pathway. Overexpression of SIRT1 deacetylase and the addition of the SIRT1 agonist resveratrol markedly reduced NF-kappaB signaling stimulated by Abeta and had strong neuroprotective effects. Our results support a glial loop hypothesis by demonstrating a critical role for microglial NF-kappaB signaling in Abeta-dependent neurodegeneration. They also implicate SIRT1 in this pathway and highlight the therapeutic potential of resveratrol and other sirtuin-activating compounds in Alzheimer disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Bromodeoxyuridine; Cells, Cultured; Genes, Reporter; Genetic Vectors; Green Fluorescent Proteins; Humans; Immunohistochemistry; Lentivirus; Lysine; Microglia; Microscopy, Fluorescence; Models, Biological; Models, Genetic; Neurons; NF-kappa B; Rats; Rats, Sprague-Dawley; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sirtuin 1; Sirtuins; Stilbenes

This paper describes a novel series of 18F-labeled polyethyleneglycol (PEG)-stilbene derivatives as potential beta-amyloid (Abeta) plaque-specific imaging agents for positron emission tomography (PET). In these series of compounds, 18F is linked to the stilbene through a PEG chain, of which the number of ethoxy groups ranges from 2 to 5. The purpose of adding PEG groups is to lower the lipophilicity and improve bioavailability. The syntheses of the "cold" compounds and the 18F-labeled PEG stilbene derivatives are successfully achieved. All of the fluorinated stilbenes displayed high binding affinities in an assay using postmortem AD brain homogenates (K(i)=2.9-6.7 nM). Labeling was successfully performed by a substitution of the mesylate group of 10a-d by [18F]fluoride giving the target compounds [18F]12a-d (EOS, specific activity, 900-1500 Ci/mmol; radiochemical purity >99%). In vivo biodistribution of these novel (18)F ligands in normal mice exhibited excellent brain penetrations and rapid washouts after an intravenous injection (6.6-8.1 and 1.2-2.6 %dose/g at 2 and 60 min, respectively). Autoradiography of postmortem AD brain sections of [18F]12a-d confirmed the specific binding related to the presence of Abeta plaques. In addition, in vivo plaque labeling can be clearly demonstrated with these 18F-labeled agents in transgenic mice (Tg2576), a useful animal model for Alzheimer's disease. In conclusion, the preliminary results strongly suggest these fluorinated PEG stilbene derivatives are suitable candidates as Abeta plaque imaging agents for studying patients with Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Drug Delivery Systems; Fluorine Radioisotopes; Metabolic Clearance Rate; Mice; Mice, Transgenic; Organ Specificity; Polyethylene Glycols; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes; Tissue Distribution

Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Brain; Humans; Magnetic Resonance Imaging; Mice; Stilbenes

A series of stilbene derivatives as potential diagnostic imaging agents targeting amyloid plaques in Alzheimer's disease (AD) were synthesized and evaluated. The syntheses of the stilbenes were successfully achieved by a simple Wadsworth-Emmons reaction between diethyl (4-nitrobenzyl)phosphonate and 4-methoxybenzaldehyde. 4-N,N-dimethylamino-4'-methyoxy and the corresponding 4-N-monomethylamino-, 4'-hydroxy stilbenes showed good binding affinities towards Abeta aggregates in vitro (K(i) < 10 nM). The (11)C labeled 4-N-methylamino-4'-hydroxystilbene, [(11)C]4, was prepared by (11)C methylation of 4-amino-4'-hydroxystilbene. The [(11)C]4 displayed a moderate lipophilicity (log P = 2.36), and showed a very good brain penetration and washout from normal rat brain after an iv injection. In vitro autoradiography of transgenic AD mouse brain sections showed a high specific labeling of beta-amyloid plaques, whereas the control sections showed no binding. Taken together the data suggest that a relatively simple stilbene derivative, [(11)C]4, N-[(11)C]methylamino-4'-hydroxystilbene, may be useful as a positron emission tomography (PET) imaging agent for mapping Abeta plaques in the brain of patients with Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Autoradiography; Brain; Carbon Radioisotopes; Isotope Labeling; Male; Mice; Mice, Transgenic; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Stilbenes; Tissue Distribution; Tomography, Emission-Computed

The identification of amyloid deposits in living Alzheimer disease (AD) patients is important for both early diagnosis and for monitoring the efficacy of newly developed anti-amyloid therapies. Methoxy-X04 is a derivative of Congo red and Chrysamine-G that contains no acid groups and is therefore smaller and much more lipophilic than Congo red or Chrysamine-G. Methoxy-X04 retains in vitro binding affinity for amyloid beta (Abeta) fibrils (Ki = 26.8 nM) very similar to that of Chrysamine-G (Ki = 25.3 nM). Methoxy-X04 is fluorescent and stains plaques, tangles, and cerebrovascular amyloid in postmortem sections of AD brain with good specificity. Using multiphoton microscopy to obtain high-resolution (1 microm) fluorescent images from the brains of living PSI/APP mice, individual plaques could be distinguished within 30 to 60 min after a single i.v. injection of 5 to 10 mg/kg methoxy-X04. A single i.p. injection of 10 mg/kg methoxy-X04 also produced high contrast images of plaques and cerebrovascular amyloid in PSI/APP mouse brain. Complementary quantitative studies using tracer doses of carbon- 11-labeled methoxy-X04 show that it enters rat brain in amounts that suggest it is a viable candidate as a positron emission tomography (PET) amyloid-imaging agent for in vivo human studies.

Topics: Alkenes; Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzene; Benzene Derivatives; Binding, Competitive; Blood-Brain Barrier; Carbon Radioisotopes; Coloring Agents; Congo Red; Disease Models, Animal; Imaging, Three-Dimensional; Male; Mice; Mice, Transgenic; Microscopy; Peptide Fragments; Plaque, Amyloid; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Stilbenes