Metformin and Alzheimer's disease: Underlying Mechanisms that Ameliorate Progression

二甲双胍和阿尔茨海默病：改善进展的潜在机制

• 批准号: 10228313
• 负责人: Hariom Yadav
• 金额: $ 9.31万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228313
• 关键词: APP-PS1; Address; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Anti-Inflammatory Agents; Antidiabetic Drugs; Attenuated; Biological; Biology of Aging; Blood - brain barrier anatomy; Brain; Butyrates; Cardiovascular system; Chronic; Clinical; Clinical Trials; Cognition; Data; Deposition; Diabetes Mellitus; Disease Marker; Disease Progression; Drug Targeting; Drug usage; Elderly; Encephalitis; Extravasation; FDA approved; Future; Geroscience; Gut Mucosa; Health; Human; Impaired cognition; Inflammation; Intervention; Intestinal permeability; Investigation; Laboratories; Leaky Gut; Link; Longevity; Mediating; Metformin; Mucositis; Mus; Nerve Degeneration; Organ; Outcome; Permeability; Pharmaceutical Preparations; Physiological; Prediabetes syndrome; Prevention; Production; Public Health; Regimen; Reporting; Research Personnel; Research Proposals; Scheme; Symptoms; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Training; Transgenic Organisms; Treatment Efficacy; United States National Institutes of Health; Vagus nerve structure; age related; blood-brain barrier permeabilization; cognitive function; comorbidity; design; fecal transplantation; fight against; gastrointestinal; gut microbiota; gut-brain axis; improved; inflammatory disease of the intestine; inflammatory marker; insight; microbial; microbiome; microbiota; mouse model; multidisciplinary; novel; novel therapeutics; pre-clinical; prevent; tau aggregation

Summary Aging is a major risk factor for Alzheimer’s disease (AD). Progression of AD has been linked with 1) an abnormally high systemic and mucosal inflammation in elderly organs, including the brain; 2) dysfunctional permeability (leakiness) in gut and blood-brain barriers (BBB); 3) suppressed autonomic (vagus) nerve activity linked with increased inflammation; and 4) increased amyloid beta (Aβ) and Tau accumulation. However, no currently available drugs target aging-related gut and BBB leakiness and/or vagus nerve suppression, to reduce inflammation. Intriguingly, metformin (a safe and clinically approved drug commonly used to treat diabetes) reduces gut and BBB leakiness and consequent inflammation to attenuate AD. This research proposal is designed to identify the mechanisms by which metformin reduces gut and BBB leakiness and/or vagus nerve function to halt inflammation and AD progression. Our preliminary studies in older mice established that metformin decreased gut leakiness and inflammation and modulated gut microbiota toward increased production of butyrate, a beneficial microbial metabolite and indicator of healthy microbiota. Metformin also improved cognitive function and reduced inflammation and AD markers in the brains of older and AD transgenic (APP/PS1) mice. These results demonstrate that metformin modulates gut-brain axis and reduces AD progression, but how metformin causes these changes is not known. We hypothesize that metformin beneficially modulates gut microbiota to suppress gut leakiness and inflammation and reduce AD progression. Mechanistically, we hypothesize that metformin-mediated suppression of inflammation in gut are mediated by (i) stimulating vagus nerve in the gut and/or (ii) reducing BBB leakiness, which reduces brain inflammation and AD progression. Three Specific Aims test this hypothesis. In Aim 1, to determine whether metformin-modified gut microbiota is causal for its effects to ameliorate AD, we will transplant fecal microbiota from metformin-treated and control AD mice into gut-cleansed APP/PS1 mice (murine model of AD), and assess markers of gut and brain inflammation, gut permeability, and AD progression. In Aim 2, we will assess whether metformin-induced changes in gut involves (i) vagus nerve and/or (ii) BBB permeability to reduce brain inflammation and AD progression. In Aim 3, we will assess whether metformin can delay or treat the pathology of AD by treating adults and older APP/PS1 mice with metformin as AD progresses. Outcomes will establish proof-of-concept and provide the critical preclinical data to support metformin as a therapy to prevent AD progression. Led by an NIH-trained new investigator, in concert with multidisciplinary experts in cutting-edge technologies, this study is timely in addressing the RFA- AG-20-044 (The Biological Mechanisms of Metformin Effects on Aging and Longevity- R01, Clinical Trial Not Allowed). With this study, we will establish the biological mechanism(s) by which metformin can be a potential new therapy for aging-related AD, a debilitating public health problem in older adults.

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