iridoids and Alzheimer-Disease

Alzheimer's Disease (AD) is the cause of around 60-70% of global cases of dementia and approximately 50 million people have been reported to suffer this disease worldwide. The leaves of olive trees (

Topics: Alzheimer Disease; Humans; Iridoid Glucosides; Iridoids; Olea; Plant Extracts; Plant Leaves; Polyphenols

Rehmannia glutinosa, the fresh or dried root of Rehmannia glutinosa (Gaertn.) Libosch. ex Fisch. & Mey., and Gardenia, the fruit of Gardenia jasminoides Ellis from Rubiaceae, both are famous traditional Chinese medicines that have been traditionally used in China. Catalpol and geniposide, as two kinds of iridoid glycosides with high activities, are the main bioactive components in Rehmannia glutinosa and Gardenia jasminoides Ellis, respectively. Over the past few decades, catalpol and geniposide have been widely studied for their therapeutic effects. The preclinical experiments demonstrated that they possessed significant neuroprotective activities against Alzheimer's disease, Parkinson's disease, stroke, and depression, etc. In this paper, the pharmacological effects and mechanisms of catalpol and geniposide on Alzheimer's disease and Parkinson's disease from 2005 to now were systematically summarized and comprehensively analyzed. At the same time, the pharmacokinetic characteristics of the analyzed compounds were also described, hoping to provide some enlightenment for the design, research, and development of iridoid glycosides.

Topics: Alzheimer Disease; Animals; Antiparkinson Agents; Drugs, Chinese Herbal; Gardenia; Humans; Iridoid Glucosides; Iridoids; Medicine, Chinese Traditional; Parkinson Disease; Rehmannia

Alzheimer's disease (AD) is the leading cause of dementia and cognitive function impairment. The multi-faced character of AD requires new drug solutions based on substances that incorporate a wide range of activities. Antioxidants, AChE/BChE inhibitors, BACE1, or anti-amyloid platelet aggregation substances are most desirable because they improve cognition with minimal side effects. Plant secondary metabolites, used in traditional medicine and pharmacy, are promising. Among these are the monoterpenes-low-molecular compounds with anti-inflammatory, antioxidant, enzyme inhibitory, analgesic, sedative, as well as other biological properties. The presented review focuses on the pathophysiology of AD and a selected group of anti-neurodegenerative monoterpenes and monoterpenoids for which possible mechanisms of action have been explained. The main body of the article focuses on monoterpenes that have shown improved memory and learning, anxiolytic and sleep-regulating effects as determined by in vitro and in silico tests-followed by validation in in vivo models.

Topics: Acetylcholine; Acetylcholinesterase; Alzheimer Disease; Animals; Anti-Anxiety Agents; Anti-Inflammatory Agents; Antioxidants; Apolipoproteins E; Cholinesterase Inhibitors; Computer Simulation; Drug Evaluation, Preclinical; Encephalitis; Humans; Iridoids; Learning; Memory; Mice; Models, Molecular; Monoterpenes; Nerve Tissue Proteins; Neuroprotective Agents; Nootropic Agents; Oxidative Stress; Phytotherapy; Polyphenols; Protein Conformation; Rats; Sleep Initiation and Maintenance Disorders

Iridoids are a class of monoterpenoid compounds constructed from 10-carbon skeleton of isoprene building units. These compounds in their aglycones and glycosylated forms exist in nature to contribute to mechanisms related to plant defenses and diverse plant-animal interactions. Recent studies have also shown that iridoids and other structurally related monoterpenes display a vast array of pharmacological effects that make them potential modulators of the Alzheimer's disease (AD). This review critically evaluates the therapeutic potential of these natural products by assessing key in vitro and in vivo data published in the scientific literature. Mechanistic approach of scrutiny addressing their effects in the Alzheimer's brain including the τ-protein phosphorylation signaling, amyloid beta (Aβ) formation, aggregation, toxicity and clearance along with various effects from antioxidant to antiinflammatory mechanisms are discussed. The drug likeness of these compounds and future prospects to consider in their development as potential leads are addressed.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Humans; Iridoids; Monoterpenes; Neuroprotective Agents

The amyloid plaques and neurofibrillary tangles found in the Alzheimer's disease (AD) brain arise as a result of self-assembly into fibrillar material of amyloid-β protein (Aβ) and hyperphosphorylated tau, respectively, through a pathological process starting with the appearance of aggregation nuclei and neurotoxic oligomers. Accordingly, the search of inhibitors of oligomer nucleation and growth is considered a promising target to prevent amyloid toxicity. In recent years, a number of dietary factors including antioxidants, vitamins, and polyphenols have been characterized for their ability to protect cells stressed by several factors including the presence of amyloid deposits as well as to inhibit amyloid self-assembly and cytotoxicity and some of them are currently in clinical trial. The present review summarizes the findings on the beneficial effects against neurodegeneration and other peripheral inflammatory and degenerative diseases of oleuropein aglycone (OLE), a natural phenol abundant in the extra virgin olive oil. The data presently available suggest that OLE could provide a protective and therapeutic effect against a number of pathologies, including AD as well as obesity, type 2 diabetes, non-alcoholic hepatitis, and other natural or experimentally-induced pathological conditions. Such a protection could result, at least in part, in a remarkable improvement of the pathological signs arising from stress conditions including oxidative stress, an excessive inflammatory response, and the presence of cytotoxic aggregated material. In particular, the recent data on the cellular and molecular correlates of OLE neuroprotection suggest it could also play a therapeutic role against AD.

Topics: Alzheimer Disease; Anti-Inflammatory Agents; Cognition Disorders; Humans; Inflammation; Iridoid Glucosides; Iridoids; Nerve Degeneration; Plaque, Amyloid

A growing body of evidence has linked two of the most common aged-related diseases: type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). It has led to the notion that drugs developed for the treatment of T2DM may be beneficial in modifying the pathophysiology of AD. As a receptor agonist of glucagon-like peptide-1 (GLP-1R), which is a newer drug class to treat T2DM, geniposide shows clear effects in inhibiting pathological processes underlying AD, such as promoting neurite outgrowth. In the present article, we review the possible molecular mechanisms of geniposide to protect the brain from pathologic damages underlying AD: reducing amyloid plaques, inhibiting τ phosphorylation, preventing memory impairment and loss of synapses, reducing oxidative stress and the chronic inflammatory response, and promoting neurite outgrowth via the GLP-1R signaling pathway. In summary, the Chinese herb geniposide shows great promise as a novel treatment for AD.

Topics: Alzheimer Disease; Animals; Diabetes Mellitus, Type 2; Humans; Iridoids; Neuroprotective Agents

Corni Fructus is a traditional Chinese herb and widely applied for treatment of age-related disorders in China. Iridoid glycoside was considered as the active ingredient of Corni Fructus. Loganin is one of the major iridoid glycosides and quality control components of Corni Fructus. Emerging evidence emphasized the beneficial effect of loganin on neurodegenerative disorders, such as Alzheimer's disease (AD). However, the detailed mechanism underlying the neuroprotective action of loganin remains to be unraveled.. To explore the improvement of loganin on cognitive impairment in 3 × Tg-AD mice and reveal the potential mechanism.. Eight-month 3 × Tg-AD male mice were intraperitoneally injected with loganin (20 and 40 mg/kg) for consecutive 21 days. Behavioral tests were used to evaluated the cognition-enhancing effects of loganin, and Nissl staining and thioflavine S staining were performed to analyze neuronal survival and Aβ pathology. Western blot analysis, transmission electron microscopy and immunofluorescence were utilized to explore the molecular mechanism of loganin in AD mice involved mitochondrial dynamics and mitophagy. Aβ. Loganin significantly mitigated the learning and memory deficit and amyloid β-protein (Aβ) deposition, and recovered synaptic ultrastructure in 3 × Tg-AD mice. Perturbed mitochondrial dynamics characterized by excessive fission and insufficient fusion were restored after loganin treatment. Meanwhile, loganin reversed the increase of mitophagy markers (LC3II, p62, PINK1 and Parkin) and mitochondrial markers (TOM20 and COXIV) in hippocampus of AD mice, and enhanced the location of optineurin (OPTN, a well-known mitophagy receptor) to mitochondria. Accumulated PINK1, Parkin, p62 and LC3II were also revealed in Aβ. Our observations confirmed that loganin enhanced cognitive function and alleviated AD pathology probably by promoting OPTN-mediated mitophagy,. Loganin might be a potential drug candidate for AD therapy via targeting mitophagy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognitive Dysfunction; Humans; Iridoids; Male; Mice; Mitophagy; Molecular Docking Simulation; Neuroblastoma; Protein Kinases; Ubiquitin-Protein Ligases

Topics: Adenosine Triphosphatases; Alzheimer Disease; Animals; Autophagosomes; Autophagy; Iridoid Glycosides; Iridoids; Mice

Topics: Alzheimer Disease; Animals; Astrocytes; Glucosides; Inflammation; Iridoids; Mice; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Proto-Oncogene Proteins c-akt; Pyrans

Topics: Alzheimer Disease; Animals; Cognitive Dysfunction; Disease Models, Animal; Female; Hippocampus; Iridoids; Mice; Mice, Transgenic; Morris Water Maze Test; Neuroprotective Agents; Proteome

Seven tacrine/CHR21 conjugates have been designed and synthesized. Compound 8-7 was confirmed as the most active AChE inhibitor with IC

Topics: Acetylcholinesterase; Alzheimer Disease; Autophagy; Drug Design; Humans; Iridoids; Molecular Structure; Structure-Activity Relationship; Tacrine

Alzheimer's disease (AD) is a devastating brain disorder characterized by neurofibrillary tangles and amyloid plaques. Inhibiting Tau protein and amyloid-beta (Aβ) production or removing these molecules is considered potential therapeutic strategies for AD. Genipin is an aglycone and is isolated from the extract of Gardenia jasminoides Ellis fruit. In this study, the effect and molecular mechanisms of genipin on the inhibition of Tau aggregation and Aβ generation were investigated. The results showed that genipin bound to Tau and protected against heparin-induced Tau fibril formation. Moreover, genipin suppressed Tau phosphorylation probably by downregulating the expression of CDK5 and GSK-3β, and activated mTOR-dependent autophagy via the SIRT1/LKB1/AMPK signaling pathway in Tau-overexpressing cells. In addition, genipin decreased Aβ production by inhibiting BACE1 expression through the PERK/eIF2α signaling pathway in N2a/SweAPP cells. These data indicated that genipin could effectively lead to a significant reduction of phosphorylated Tau level and Aβ generation in vitro, suggesting that genipin might be developed into an effective therapeutic complement or a potential nutraceutical for preventing AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line, Tumor; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Iridoids; Mice; Mice, Transgenic; Phosphorylation; Protein Structure, Tertiary; tau Proteins

The aim of this study is to investigate the protective effects as well as the underlying molecular mechanisms of geniposide in APP/PS1 transgenic mice.. APP/PS1 mice were subjected to intragastric administration of geniposide (50 mg/kg/d) for 8 weeks (including a 2-week behavior test). The novel object recognition (NOR) and the Morris water maze (MWM) tests were used for behavioral assessments. Aβ1-40 plaques in mice cortices and hippocampi are visualized with immunohistochemistical staining. ELISA was used to quantify the levels of soluble Aβ1-40 and Aβ1-42 in the hippocampus. Western blot was used to detect p-Akt/Akt, p-mTOR/mTOR and p-4E-BP1/4E-BP1 levels. The relative mRNA levels of Akt, mTOR and 4E-BP1 were quantified using real-time PCR (RT-PCR).. Geniposide alleviated cognitive impairment by improving the ability of novel object exploration, spatial memory, and reduced the level of Aβ in the brain of APP/PS1 mice. Geniposide possibly regulates mTOR-related proteins through modification of phosphorylation. Geniposide markedly lowered p-mTOR and p-Akt expressions while elevating p-4E-BP1 expression. Geniposide obviously reduced the relative mRNA levels of Akt and mTOR and increased the relative mRNA level of 4E-BP1.. Geniposide is able to alleviate cognitive impairments and cerebral damage in APP/PS1 mice, with its neuroprotective effects likely mediated via modulation of the mTOR signaling pathway.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Cortex; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Iridoids; Male; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Peptide Fragments; Plaque, Amyloid; Signal Transduction; TOR Serine-Threonine Kinases

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Binding Sites; Cell Survival; Drug Design; Inhibitory Concentration 50; Iridoids; Molecular Docking Simulation; Neuroprotective Agents; PC12 Cells; Peptide Fragments; Protein Structure, Tertiary; Rats; Structure-Activity Relationship

Geniposide, an iridoid glycoside extract from the gardenia fruit, is used in traditional Chinese medicine to alleviate symptoms of liver and inflammatory diseases. Geniposide activates GLP-1 receptors, known to modulate the activity of mechanistic target of rapamycin (mTOR), a key kinase regulating energy balance, proliferation, and survival in cells. mTOR activation inhibits autophagy, which is often disrupted in age-related diseases. Modulation of mTOR function to increase autophagy and inhibit apoptosis is involved in the protective effects of pharmacologic agents targeting diabetes and Alzheimer's disease (AD). We investigated whether such mechanism could mediate geniposide's neuroprotective effects in the APP/PS1 mouse model of AD. Eight-week treatment with geniposide improved cognitive scores in behavioral tests, reduced amyloid-β 1-40 plaque deposition, and reduced soluble Aβ1-40 and Aβ1-42 levels in the APP/PS1 mouse brain.This also showed increased p-Akt/Akt, p-mTOR/mTOR and decreased p-4E-BP1/4E-BP1 expression, and these patterns were partially reversed by geniposide. Evidence for enhanced autophagy, denoted by increased expression of LC3-II and Beclin1, was also seen after treatment with geniposide. Our data suggests that down regulation of mTOR signaling, leading to enhanced autophagy and lysosomal clearance of Aβ fibrils, underlies the beneficial effects of geniposide against neuropathological damage and cognitive deficits characteristic of AD.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Protein Precursor; Animals; Autophagy; Behavior, Animal; Cognitive Dysfunction; Down-Regulation; Gene Expression Regulation; Humans; Iridoids; Mice; Mice, Transgenic; Peptide Fragments; Plaque, Amyloid; Random Allocation; TOR Serine-Threonine Kinases

Herbal extracts have been extensively used worldwide for their application on memory improvement, especially among aged and memory-deficit populations. In the present study, the memory loss induced by human Abeta protein over-expression in fruitfly Alzheimer's disease (AD) model was rescued by multiple extracts from Gardenia jasminoides. Three extracts that rich with gardenia yellow, geniposide, and gardenoside components showed distinct rescue effect on memory loss. Further investigation on adding gardenoside into a formula of Ganoderma lucidum, Panax notoginseng and Panax ginseng (GPP) also support its therapeutic effects on memory improvement. Interestingly, the application of GPP and gardenoside did not alter the accumulation of Abeta proteins but suppressed the expression of immune-related genes in the brain. These results revealed the importance and relevancy of anti-inflammation process and the underlying mechanisms on rescuing memory deficits, suggesting the potential therapeutic use of the improved GPP formulation in improving cognition in defined population in the future.

Topics: Alzheimer Disease; Animals; Antimicrobial Cationic Peptides; Brain; Cognition; Disease Models, Animal; Drosophila; Drosophila Proteins; Gardenia; Gene Expression Regulation; Immunity, Innate; Iridoids; Plant Extracts; Polymerase Chain Reaction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory deficits and cognitive decline. Amyloid-β (Aβ) deposition and cholinergic defect are widely thought to be the underlying mechanism of learning and memory impairment. Geniposide, which is the main active component of the traditional Chinese herbal Gardenia jasminoides Ellis, elicits neuroprotective effects by alleviating inflammation responses and oxidative damages. In this study, we investigated the protective effect of geniposide on levels of cholinergic markers, RAGE, RAGE-dependent signalling pathways and amyloid accumulation in the APPswe/PS1dE9 AD model mouse. Geniposide suppressed MAPK signaling over-activation mediated by Aβ-RAGE interaction, resulting in reduced Aβ accumulation and amelioration of cholinergic deficits in the cerebral hippocampus. Furthermore, geniposide inhibited the toxic effect of oligomeric Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Animals; Brain; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Iridoids; Male; MAP Kinase Signaling System; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Neuroprotective Agents; Nootropic Agents; Peptide Fragments; Receptor for Advanced Glycation End Products

Our previous studies have shown that geniposide plays an essential role in glucose-stimulated insulin secretion from pancreatic β cells and also regulates the metabolism of Aβ and its deposition in neurons. In this study, we reported that insulin deficiency induced significant increase of tau phosphorylation. Administration of geniposide for 4 weeks significantly decreased the phosphorylated level of tau and the acceleration of GSK-3β phosphorylation in the brain of APP/PS1 transgenic mice induced by insulin deficiency. We also observed that geniposide decreased the phosphorylation of tau protein directly and increased the phosphorylation of Akt in primary cultured cortical neurons. Furthermore, geniposide enhanced the role of insulin on the phosphorylation of Akt, GSK-3β, and tau in primary cultured cortical neurons. And these effects of geniposide in cortical neurons could be prevented by preincubation with LY294002, an inhibitor of PI3K. Taken together, our findings provide a mechanistic and perhaps a foundational link between diabetes and Alzheimer's disease and are consistent with the notion that geniposide might play an essential role on the phosphorylation of tau protein via enhancing insulin signaling and may convey a therapeutic benefit in Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Humans; Insulin; Iridoids; Mice; Mice, Transgenic; Phosphorylation; Presenilin-1; tau Proteins

We evaluated the major active components isolated from Corni Fructus: loganin, morroniside, and 7-O-galloyl-D-sedoheptulose as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) for use in Alzheimer's disease treatment. These compounds exhibited predominant cholinesterase (ChEs) inhibitory effects with IC50 values of 0.33, 3.95, and 10.50 ± 1.16 µM, respectively, for AChE, and 33.02, 37.78, and 87.94 ± 4.66 µM, respectively, for BChE. Kinetics studies revealed that loganin and 7-O-galloyl-D-sedoheptulose inhibited AChE with characteristics typical of mixed inhibitors, while morroniside was found to be a noncompetitive inhibitor against AChE and also exerted mixed BChE inhibitory activities. For BACE1, loganin showed noncompetitive type inhibitory effects, while morroniside and 7-O-galloyl-D-sedoheptulose were found to be mixed inhibitors. Furthermore, these compounds exhibited dose-dependent inhibitory activity with ONOO(-)-mediated protein tyrosine nitration. Molecular docking simulation of these compounds demonstrated negative binding energies for ChEs, and BACE1, indicating high affinity and tighter binding capacity for the active site of the enzyme. Loganin was the most potent inhibitor against both ChEs and BACE1. The data suggest that these compounds together can act as a triple inhibitor of AChE, BChE, and BACE1, providing a preventive and therapeutic strategy for Alzheimer's disease treatment.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Butyrylcholinesterase; Cholinesterase Inhibitors; Cornus; Drug Discovery; Glycosides; Heptoses; Iridoids; Kinetics; Molecular Docking Simulation; Protein Binding

The receptor for advanced glycation end products (RAGE)-mediated signaling pathway is related to Aβ-induced pathogenic responses. Geniposide, a pharmacologically active component purified from gardenia fruit, could attenuate the oligomeric Aβ(1-42)-induced inflammatory response by blocking the ligation of Aβ to RAGE and suppressing the RAGE-mediated signaling in vitro. Here, we investigated whether geniposide can exert protective effects on the neuroinflammation and memory deficits in an Alzheimer's disease (AD) mouse model. The results indicate that geniposide treatment significantly suppresses RAGE-dependent signaling (activation of ERK and IκB/NF-κB), the production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and cerebral Aβ accumulation in vivo. Furthermore, we demonstrate that geniposide augments synaptic plasticity by attenuating the Aβ-induced reduction of long-term potentiation and increasing the miniature excitatory postsynaptic current (mEPSC) amplitude and frequency in hippocampal neurons. In addition, the intragastric administration of geniposide improves learning and memory in APP/PS1 mice. Taken together, these studies indicate that geniposide has profound multifaceted neuroprotective effects in an AD mouse model. Geniposide demonstrates its neuroprotection by inhibiting inflammation, ameliorating amyloid pathology and improving cognition. Thus, geniposide may be a potential therapeutic agent for halting and preventing AD progression.

Topics: Alzheimer Disease; Animals; Cells, Cultured; Disease Models, Animal; Iridoids; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Treatment Outcome

Amyloid-ß (Aß) fragments, oligomeric Aß aggregates, and pyroglutamylated-Aß peptides, as well as epigenetic mechanisms and autophagy dysfunction all appear to contribute in various ways to Alzheimer's disease progression. We previously showed that dietary supplementation of oleuropein aglycone, a natural phenol abundant in the extra virgin olive oil, can be protective by reducing Aß42 deposits in the brain of young and middle-aged TgCRND8 mice. Here, we extended our study to aged TgCRND8 mice showing increased pE3-Aß in the brain deposits. We report that oleuropein aglycone is active against glutaminylcyclase-catalyzed pE3-Aß generation reducing enzyme expression and interferes both with Aß42 and pE3-Aß aggregation. Moreover, the phenol astonishingly activates neuronal autophagy even in mice at advanced stage of pathology, where it increases histone 3 and 4 acetylation, which matches both a decrease of histone deacetylase 2 expression and a significant improvement of synaptic function. The occurrence of these functional, epigenetic, and histopathologic beneficial effects even at a late stage of the pathology suggests that the phenol could be beneficial at the therapeutic, in addition to the prevention, level.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Autophagy; Brain; Depression, Chemical; Dietary Supplements; Disease Progression; Epigenesis, Genetic; Female; Histone Deacetylase 2; Histones; Iridoid Glucosides; Iridoids; Male; Mice, Transgenic; Olive Oil; Peptide Fragments; Plant Oils; Protein Aggregates

Our previous studies have shown that geniposide plays an essential role in glucose-stimulated insulin secretion from pancreatic β cells and also antagonizesAβ1-42-induced cytotoxicity examined using a primary cortical neuron assay. However, the mechanism by which geniposide appears to regulate insulin signaling in the brain is presently not well understood. In this study, we administered streptozotocin (STZ) to induce insulin-deficiency in an AD transgenic mouse model, and investigated the effects of geniposide on the β-amyloidogenic processing of amyloid precursor protein (APP) using in vitro and in vivo models. Our results indicate that treatment with STZ (90 mg/kg, i.p., once daily for two consecutive days) induced significant reduction in peripheral and brain insulin levels in both wild-type and APP/PS1 transgenic mice. Administration of geniposide for 4 weeks significantly decreased the concentrations of cerebral β-amyloid peptides (Aβ1-40 and Aβ1-42) in STZ-treated AD mice. Further experiments showed that geniposide up-regulated the protein levels of β-site APP cleaving enzyme (BACE1) and insulin-degrading enzyme (IDE), and decreased the protein levels of ADAM10 when examined using a primary cultured cortical neuron assay and in STZ-induced AD mice. Meanwhile, geniposide also directly enhanced the effects of insulin by reducing Aβ1-42 levels in primary cultured cortical neurons. Taken together, our findings provide a mechanistic link between diabetes and AD, and is consistent with the notion that geniposide might play an important role on APP processing via enhancing insulin signaling and may convey a therapeutic benefit in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cells, Cultured; Diabetes Mellitus, Experimental; Disease Models, Animal; Humans; Insulin; Iridoids; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Presenilin-1

We have previously demonstrated that geniposide attenuates the production of Aβ1-42 both in vitro and in vivo via enhancing leptin receptor signaling. But the role played by geniposide in the phosphorylation of tau and its underlying molecular mechanisms remain unclear. In this study, we investigated the effect of geniposide on the phosphorylation of tau and the role of leptin signaling in this process. Our data suggested that, accompanied by the up-regulation of leptin receptor expression, geniposide significantly decreased the phosphorylation of tau in rat primary cultured cortical neurons and in APP/PS1 transgenic mice, and this geniposide-induced decrease of tau phosphorylation could be prevented by leptin antagonist (LA). Furthermore, LA also prevented the phosphorylation of Akt at Ser-473 site and GSK-3β at Ser-9 site induced by geniposide. All these results indicate that geniposide may regulate tau phosphorylation through leptin signaling, and geniposide may be a promising therapeutic compound for the treatment of Alzheimer's disease in the future.

Topics: Alzheimer Disease; Animals; Gene Expression Regulation; Glycogen Synthase Kinase 3 beta; Iridoids; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Phosphorylation; Rats; Receptors, Leptin; Signal Transduction; tau Proteins

Translational research needs valid animal models of disease to discover new pathogenetic aspects and treatments. In Alzheimer's disease (AD), transgenic models are of great value for AD research and drug testing.. It was the aim of this study to analyze the power of dietary polyphenols against neurodegeneration by investigating the effects of oleuropein aglycone (OLE), the main phenol in the extra virgin olive oil (EVOO), a key component of the Mediterranean diet (MD), in a mouse model of amyloid-β deposition.. TgCRND8 mice (3.5 months old), expressing the mutant KM670/671NL+V717F h-βAPP695 transgene, and wild-type (wt) mice were used to study in vivo the effects of an 8-week dietary supplementation with OLE (50 mg/kg of diet) [Grossi et al: PLoS One 2013;8:e71702], following the European Communities Council Directive 86/609 (DL 116/92) and National Guidelines (permit number: 283/2012-B).. OLE administration ameliorates memory dysfunction, raises a significant autophagic response in the cortex and promotes the proliferation of newborn cells in the subgranular zone of the dentate gyrus of the hippocampus.. Our findings support the beneficial effects of EVOO and highlight the possibility that continuous intake of high doses of OLE, both as a nutraceutical or as a food integrator, may prevent/delay the appearance of AD and reduce the severity of its symptoms.

Topics: Alzheimer Disease; Animal Feed; Animals; Brain; Diet, Mediterranean; Disease Models, Animal; Humans; Iridoid Glucosides; Iridoids; Mice, Transgenic; Neuroprotective Agents; Olive Oil; Plant Oils; Translational Research, Biomedical

Intracerebral-ventricular (ICV) injection of streptozotocin (STZ) induces an insulin-resistant brain state that may underlie the neural pathogenesis of sporadic Alzheimer disease (AD). Our previous work showed that prior ICV treatment of glucagon-like peptide-1 (GLP-1) could prevent STZ-induced learning memory impairment and tau hyperphosphorylation in the rat brain. The Chinese herbal medicine geniposide is known to relieve symptoms of type 2 diabetes. Because geniposide is thought to act as a GLP-1 receptor agonist, we investigated the potential therapeutic effect of geniposide on STZ-induced AD model in rats. Our result showed that a single injection of geniposide (50 μM, 10 μL) to the lateral ventricle prevented STZ-induced spatial learning deficit by about 40% and reduced tau phosphorylation by about 30% with Morris water maze test and quantitative immunohistochemical analysis, respectively. It has been known that tau protein can be phosphorylated by glycogen synthase kinase-3 (GSK3) and STZ can increase the activity of GSK3β. Our result with Western blot analysis showed that central administration of geniposide resulted in an elevated expression of GSK3β(pS-9) but suppressed GSK3β(pY-216) indicating that geniposide reduced STZ-induced GSK3β hyperactivity. In addition, ultrastructure analysis showed that geniposide averted STZ-induced neural pathology, including paired helical filament (PHF)-like structures, accumulation of vesicles in synaptic terminal, abnormalities of endoplasmic reticulum (ER) and early stage of apoptosis. In summary, our study suggests that the water soluble and orally active monomer of Chinese herbal medicine geniposide may serve as a novel therapeutic agent for the treatment of sporadic AD.

Topics: Alzheimer Disease; Animals; Antibiotics, Antineoplastic; Apoptosis; Disease Models, Animal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Iridoids; Male; Maze Learning; Memory Disorders; Microscopy, Electron, Transmission; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction; Streptozocin; tau Proteins; Vacuoles

In previous study, we have screened the effective fraction against Alzheimer's disease (AD-EF) from the extracts of roots and rhizomes of Valeriana amurensis, based on which neuroprotective active constituents from AD-EF were investigated. Six new compounds 1-6, including four iridoids (xiecaoside A-C and xiecaoline A), one pinane-type monoterpeneglucoside (xiecaoside D), and one phenylpropanoid glycoside (xiecaoside E) were isolated together with 11 known compounds 7-17. The structures of 1-6 were elucidated by their spectroscopic data. The protective effects of compounds 1-17 on PC12 cells with neurotoxicity induced by amyloid-beta 1-42 (Aβ(1-42)) was also investigated, respectively. Consequently, compound 6 and lignans 11-17 were responsible for protecting against Aβ-induced toxicity in PC12 cells.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Survival; Iridoids; Lignans; Magnetic Resonance Spectroscopy; Molecular Structure; Neuroprotective Agents; PC12 Cells; Plant Extracts; Plant Roots; Plants, Medicinal; Rats; Reference Values; Rhizome; Valerian

Oxidative stress and mitochondrial dysfunction appear early and contribute to the disease progression in Alzheimer's disease (AD), which can be detected extensively in AD patients brains as well as in transgenic AD mice brains. Thus, treatments that result in attenuation of oxidative stress and mitochondrial dysfunction may hold potential for AD treatment. Geniposide, a pharmacologically active component purified from gardenia fruit, exhibits anti-oxidative, antiinflammatory and other important therapeutic properties. However, whether geniposide has any protective effect on oxidative stress and mitochondrial dysfunction in AD transgenic mouse model has not yet been reported. Here, we demonstrate that intragastric administration of geniposide significantly reduces oxidative stress and mitochondrial dysfunction in addition to improving learning and memory in APP/PS1 mice. Geniposide exerts protective effects on mitochondrial dysfunction in APP/PS1 mice through suppressing the mitochondrial oxidative damage and increasing the mitochondrial membrane potential and activity of cytochrome c oxidase. These studies indicate that geniposide may attenuate memory deficits through the suppression of mitochondrial oxidative stress. Thus, geniposide may be a potential therapeutic reagent for halting and preventing AD progress.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Disease Models, Animal; Electron Transport Complex IV; Humans; Iridoids; Male; Malondialdehyde; Maze Learning; Membrane Potential, Mitochondrial; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Nootropic Agents; Oxidative Stress; Presenilin-1; Random Allocation; Reactive Oxygen Species

Our former studies have suggested that TongLuoJiuNao (TLJN) is clinically efficacious in the treatment of dementia and improving learning and memory in AD models. When Aβ aggregated with oligomer, it is known to be able to induce cellular toxicity as well as cognitive impairment. We tested the possibility that TLJN affects the formation of Aβ oligomers. In our experiment, TLJN improved cell viability, inhibited LDH release, and promoted the outgrowth of neurites of neurons treated with Aβ. Geniposide, the main component of TLJN, could increase the cell viability of SY5Y-APP695sw cells. The cytotoxicity of pretreated Aβ with geniposide was decreased in a dose-dependent manner. SDS-PAGE and Western blotting showed that geniposide and TLJN stimulated Aβ oligomer assembly. Compared with the control, more and longer fibrils of Aβ in the presence of geniposide were observed under electron microscope though the fibrils became less sensitive to thioflavin T staining. In sum, geniposide is able to protect neurons from Aβ-induced damage by remodeling Aβ.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Cell Line; Cell Survival; Drugs, Chinese Herbal; Hippocampus; Humans; Iridoids; Neurons; Neuroprotective Agents; Rats

To investigate the therapeutic effects and acting mechanism of a combination of Chinese herb active components, i.e., a combination of baicalin, jasminoidin and cholic acid (CBJC) on Alzheimer's disease (AD).. Male rats were intracerebroventricularly injected with ibotenic acid (IBO), and CBJC was orally administered. Therapeutic effect was evaluated with the Morris water maze test, FDG-PET examination, and histological examination, and the acting mechanism was studied with DNA microarrays and western blotting.. CBJC treatment significantly attenuated IBO-induced abnormalities in cognition, brain functional images, and brain histological morphology. Additionally, the expression levels of 19 genes in the forebrain were significantly influenced by CBJC; approximately 60% of these genes were related to neuroprotection and neurogenesis, whereas others were related to anti-oxidation, protein degradation, cholesterol metabolism, stress response, angiogenesis, and apoptosis. Expression of these genes was increased, except for the gene related to apoptosis. Changes in expression for 5 of these genes were confirmed by western blotting.. CBJC can ameliorate the IBO-induced dementia in rats and may be significant in the treatment of AD. The therapeutic mechanism may be related to CBJC's modulation of a number of processes, mainly through promotion of neuroprotection and neurogenesis, with additional promotion of anti-oxidation, protein degradation, etc.

Topics: Alzheimer Disease; Animals; Cholic Acid; Dementia; Disease Models, Animal; Drug Combinations; Drugs, Chinese Herbal; Flavonoids; Humans; Ibotenic Acid; Iridoids; Male; Neuroprotective Agents; Oligonucleotide Array Sequence Analysis; Rats

Composed of Ginsenoside Rg1 and Geniposide, the herbal medicine TongLuoJiuNao (TLJN) injection liquid has anti-inflammatory properties and can improve learning and memory in mice. Recently, TLJN has been used to treat the patients with cerebral ischemic stroke and vascular dementia, which significantly increase the risk of developing Alzheimer's disease (AD) in the early human beings. Although beneficial effects of TLJN have been reported in the vascular-associated brain disorders, the roles of TLJN in AD brains are still not clear. In this study, we chronically administered TLJN in amyloid precursor protein (APP) Swedish mutant transgenic mice (APP23) from 6 months old of age, which is at the onset of Aβ plaques, to 12 months old. We found that TLJN significantly decreased Aβ production and deposition in the brain of APP23 mice. Furthermore, we observed that TLJN down-regulated the levels and activity of β-secretase 1 (BACE1) protein as well as the expression levels of γ-secretase complex components: PS1, nicastrin and anterior pharynx-defective 1 (APH1) but not presenilin enhancer 2 (PEN2). The results suggest an inhibitory effect of TLJN on amyloidogenic APP processing by down-regulating the cleavage enzymes BACE1 and γ-secretase.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Central Nervous System Agents; Drug Combinations; Drugs, Chinese Herbal; Endopeptidases; Ginsenosides; Humans; Iridoids; Male; Membrane Glycoproteins; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Presenilin-1; Stroke

The presence of amyloid aggregates of the 42 amino acid peptide of amyloid beta (Aβ42) in the brain is the characteristic feature of Alzheimer's disease (AD). Amyloid beta (Aβ deposition is also found in muscle fibers of individuals affected by inclusion body myositis (sIBM), a rare muscular degenerative disease affecting people over 50. Both conditions are presently lacking an effective therapeutic treatment. There is increasing evidence to suggest that natural polyphenols may prevent the formation of toxic amyloid aggregates; this applies also to oleuropein aglycone (OLE), the most abundant polyphenol in extra virgin olive oil, previously shown to hinder amylin and Aβ aggregation. Here we evaluated the ability of OLE to interfere with Aβ proteotoxicity in vivo by using the transgenic CL2006 and CL4176 strains of Caenorhabditis elegans, simplified models of AD and of sIBM, which express human Aβ in the cytoplasm of body wall muscle cells. OLE-fed CL2006 worms displayed reduced Aβ plaque deposition, less abundant toxic Aβ oligomers, remarkably decreased paralysis and increased lifespan with respect to untreated animals. A protective effect was also observed in CL4176 worms but only when OLE was administered before the induction of the Aβ transgene expression. These effects were specific, dose-related, and not mediated by the known polyphenolic anti-oxidant activity, suggesting that, in this model organism, OLE interferes with the Aβ aggregation skipping the appearance of toxic species, as already shown in vitro for Aβ42.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Caenorhabditis; Disease Models, Animal; Humans; Iridoid Glucosides; Iridoids; Peptide Fragments; Pyrans; Vasodilator Agents

A new lignan glucoside, (+)-(7S,8R,8'R)-lyoniresinol 9-O-β-D-(6″-O-trans-sinapoyl)glucopyranoside (1), and a new iridoid glucoside, 10-O-trans-sinapoylgeniposide (2), together with eight known compounds, were isolated from the fruits of Gardenia jasminoides Ellis. The structures of the isolates were elucidated by extensive spectroscopic studies, including UV, IR, 1D and 2D NMR, ESI-MS, HR-ESI-MS, and CD experiments. The short-term-memory-enhancement activities of some compounds were evaluated on an Aβ transgenic drosophila model.

Topics: Alzheimer Disease; Animals; Animals, Genetically Modified; Disease Models, Animal; Drosophila; Fruit; Gardenia; Glycosides; Humans; Iridoids; Lignans; Memory, Short-Term; Molecular Structure; Nootropic Agents; Phytotherapy; Plant Extracts

Amyloid beta peptide (Abeta) aggregation leads to the senile plaque formation, a process that is strongly influenced by oxidative stress and is considered as the molecular basis of various neurodegenerative diseases, such as Alzheimer's disease (AD). Endogenous antioxidants or dietary derived compounds may down-regulate this process. In this study, the interaction of two antioxidants, oleuropein (OE) and melatonin (M), with Abeta is monitored through nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry. The concerted application of these two analytical techniques provides new experimental evidence and residue-specific insights into the interacting Abeta peptide amino acids that are implicated in this process. Both antioxidant compounds interact in a similar way with the peptide and cause chemical shift variations. The most pronounced resonance changes have been observed for the 1H-15N signals of N-terminal region and Leu17-Phe20 residues, as monitored by NMR titration studies.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Humans; Iridoid Glucosides; Iridoids; Melatonin; Nuclear Magnetic Resonance, Biomolecular; Peptide Fragments; Pyrans

Amyloid aggregation starts with the initial misfolding of peptide/protein precursors, with subsequent structural rearrangement into oligomers and protofibrils; the latter eventually organize into fibrils with shared basic structural features, found deposited in amyloid diseases. Mounting evidence indicates early oligomers as the most toxic amyloid species; accordingly, the search of inhibitors of their growth is considered a promising target to prevent amyloid toxicity. We recently showed that oleuropein aglycon, a polyphenol abundant in the extra virgin olive oil, interferes with the aggregation of amylin (involved in type-2 diabetes), eliminating its cytotoxicity. Here we report that oleuropein aglycon also hinders amyloid aggregation of Aβ(1-42) and its cytotoxicity, suggesting a general effect of such polyphenol. In particular, by using a wide panel of different spectroscopic, immunologic, cell viability and imaging techniques we provide a more detailed description of Aβ(1-42) structural modifications arising in the presence of the inhibitor and the resulting cytotoxicity. We here report that the polyphenol eliminates the appearance of early toxic oligomers favouring the formation of stable harmless protofibrils, structurally different from the typical Aβ(1-42) fibrils. We also show that oleuropein aglycon is maximally effective when is present at the beginning of the aggregation process; furthermore, when added to preformed fibrils, it does not induce the release of toxic oligomers but, rather, neutralizes any residual toxicity possibly arising from the residual presence of traces of soluble oligomers and other toxic aggregates. The possible use of this polyphenol as anti-aggregation molecule is discussed in the light of these data.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Humans; Iridoid Glucosides; Iridoids; Neuroprotective Agents; Peptide Fragments; Plant Extracts; Plaque, Amyloid; Polymers; Polyphenols; Pyrans

Oxidative stress plays a critical role in the pathogenic cascade leading to neuronal degeneration in AD. Consequently, the induction of endogenous antioxidative proteins by antioxidants seems to be a very reasonable strategy for delaying the disease's progression. In previous work, we identified the neurotrophic and neuroprotective effects of geniposide, which result from the activation of glucagon-like peptide 1 receptor (GLP-1R). In this study, we explore the role of PI3 kinase signaling pathway in the neuroprotection of geniposide in PC12 cells.. Cell viability was determined by MTT assay. Apoptosis was detected by Hoechst and PI double staining. The protein expression of Bcl-2 and phosphorylation of Akt308, Akt473, GSK-3beta, and PDK1 was measured by Western blot.. Geniposide induced the expression of the antiapoptotic protein Bcl-2, which inhibited apoptosis in PC12 cells induced by H(2)O(2), and this effect could be inhibited by preincubation with LY294002, a selective inhibitor of PI3K. Furthermore, geniposide enhanced the phosphorylation of Akt308, Akt473, GSK-3beta and PDK1 under conditions of oxidative stress.. These results demonstrate that the PI3K signaling pathway is involved in the neuroprotection of geniposide in PC12 cells against the oxidative damage induced by H(2)O(2) in PC12 cells.

Topics: Alzheimer Disease; Animals; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hydrogen Peroxide; Iridoids; Neurons; Neuroprotective Agents; Oxidants; Oxidative Stress; PC12 Cells; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Rats; Receptors, Glucagon; Signal Transduction

Seven new iridoid glucosides, 6''-O-trans-sinapoylgenipin gentiobioside (1), 6''-O-trans-p-coumaroylgenipin gentiobioside (2), 6''-O-trans-cinnamoylgenipin gentiobioside (3), 6'-O-trans-p-coumaroylgeniposide (4), 6'-O-trans-p-coumaroylgeniposidic acid (5), 10-O-succinoylgeniposide (6), and 6'-O-acetylgeniposide (7), two new monoterpenoids, 11-(6-O-trans-sinapoylglucopyranosyl)gardendiol (8) and 10-(6-O-trans-sinapoylglucopyranosyl)gardendiol (9), and three known ones, 6'-O-trans-sinapoylgeniposide (10), geniposide (11), and 10-O-acetylgeniposide (12), were isolated from the fruit of Gardenia jasminoides. The structures of these compounds were elucidated on the basis of 1D and 2D NMR spectra analyses. Furthermore, short-term memory assays on an Abeta transgenic drosophila model showed that compounds 4 and 6-12 can improve the short-term memory capacity to varying degrees, with compounds 4 and 7 being the most active ones, suggesting that these compounds may have a potential antagonism effect against Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Animals, Genetically Modified; Disease Models, Animal; Drosophila; Fruit; Gardenia; Iridoids; Memory, Short-Term; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Stereoisomerism