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Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease.

ABSTRACT: BACKGROUND: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 A?40 levels and activities of daily living (ADL) scores. METHODS:For this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF A?42 <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. RESULTS: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 A?42 levels during the 52-week trial, but did not alter tau levels. CONCLUSIONS: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. TRIAL REGISTRATION:ClinicalTrials.gov NCT01504854.

SUBMITTER: Moussa C

PROVIDER: S-EPMC5234138 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease.

Moussa Charbel C Hebron Michaeline M Huang Xu X Ahn Jaeil J Rissman Robert A RA Aisen Paul S PS Turner R Scott RS

Journal of neuroinflammation 20170103 1

<h4>Background</h4>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.<h4>Methods</h4>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-treate ...[more]

PMID: 28086917

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Project description:Aims: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cerebral amyloid β (Aβ) deposition and tau pathology. The AD-mediated degeneration of the brain neuro-signaling pathways, together with a potential peripheral amyloid accumulation, may also result in the derangement of the peripheral nervous system, culminating in detrimental effects on other organs, including the heart. However, whether and how AD pathology modulates cardiac function, neurotrophins, innervation, and amyloidosis is still unknown. Here, we report for the first time that cardiac remodeling, amyloid deposition, and neuro-signaling dysregulation occur in the heart of Tg2576 mice, a widely used model of AD and cerebral amyloidosis. Methods and Results: Echocardiographic analysis showed significant deterioration of left ventricle function, evidenced by a decline of both ejection fraction and fraction shortening percentage in 12-month-old Tg2576 mice compared to age-matched WT littermates. Tg2576 mice hearts exhibited an accumulation of amyloid aggregates, including Aβ, an increase in interstitial fibrosis and severe cardiac nervous system dysfunction. The transgenic mice also showed a significant decrease in cardiac nerve fiber density, including both adrenergic and regenerating nerve endings. This myocardial denervation was accompanied by a robust reduction in NGF and BDNF protein expression as well as GAP-43 expression (regenerating fibers) in both the brain and heart of Tg2576 mice. Accordingly, cardiomyocytes and neuronal cells challenged with Aβ oligomers showed significant downregulation of BDNF and GAP-43, indicating a causal effect of Aβ on the loss of cardiac neurotrophic function. Conclusions: Overall, this study uncovers possible harmful effects of AD on the heart, revealing cardiac degeneration induced by Aβ through fibrosis and neuro-signaling pathway deregulation for the first time in Tg2576 mice. Our data suggest that AD pathology can cause deleterious effects on the heart, and the peripheral neurotrophic pathway may represent a potential therapeutic target to limit these effects.

Dataset Information

Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease.

Publications

Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease.

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