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.

总结 衰老是阿尔茨海默病（AD）的主要危险因素。AD的进展与1） 老年器官（包括大脑）中异常高的全身和粘膜炎症; 2）功能障碍 肠和血脑屏障（BBB）的渗透性（泄漏）; 3）抑制自主神经（迷走神经）活动 与炎症增加相关;和4）淀粉样蛋白β（Aβ）和Tau积累增加。但没有 目前可用的药物靶向衰老相关的肠道和BBB渗漏和/或迷走神经抑制，以减少 炎症有趣的是，二甲双胍（一种安全且临床批准的常用于治疗糖尿病的药物） 减少肠道和BBB渗漏和随之而来的炎症以减轻AD。该研究计划是 旨在确定二甲双胍减少肠道和BBB渗漏和/或迷走神经的机制 阻止炎症和AD进展的功能。我们对老年小鼠的初步研究表明， 二甲双胍减少肠道渗漏和炎症，调节肠道微生物群以增加产量 丁酸盐，一种有益的微生物代谢物和健康微生物群的指标。代谢也有所改善 老年人和AD转基因人（APP/PS1）大脑中的认知功能和炎症及AD标志物减少 小鼠这些结果表明，二甲双胍调节肠-脑轴，减少AD进展，但如何 二甲双胍引起这些变化的原因尚不清楚。我们假设二甲双胍有益地调节肠道 微生物群抑制肠道渗漏和炎症并减少AD进展。机械地，我们 假设二甲双胍介导肠道炎症抑制是通过（i）刺激迷走神经 神经和/或（ii）减少BBB渗漏，这减少脑炎症和AD进展。三 具体目标检验了这一假设。在目标1中，为了确定二甲双胍修饰的肠道微生物群是否是因果关系， 为了改善AD，我们将从二甲双胍治疗和对照AD小鼠中移植粪便微生物群 进入肠道清洁的APP/PS1小鼠（AD的鼠模型），并评估肠道和脑炎症、肠道炎症和脑损伤的标志物。 渗透性和AD进展。在目标2中，我们将评估二甲双胍诱导的肠道变化是否涉及 (i)迷走神经和/或（ii）BBB渗透性，以减少脑炎症和AD进展。在目标3中，我们 通过治疗成年和老年APP/PS1小鼠，评估二甲双胍是否可以延迟或治疗AD的病理学 二甲双胍治疗AD结果将建立概念验证，并提供关键的临床前 数据支持二甲双胍作为预防AD进展的治疗。在一位接受过NIH培训的新研究员的带领下， 与尖端技术的多学科专家合作，这项研究及时解决了RFA问题- AG-20-044（二甲双胍对衰老和长寿影响的生物学机制-R 01，临床试验编号 允许）。通过这项研究，我们将建立二甲双胍可能成为一种潜在的 新的治疗衰老相关的AD，一个衰弱的公共卫生问题，在老年人。