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: 10453857
• 负责人: Hariom Yadav
• 金额: $ 29.45万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453857
• 关键词: Metformin; Alzheimer; disease; Underlying; Mechanisms

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.

摘要 衰老是阿尔茨海默病(AD)的主要危险因素。AD的进展与1)和 包括大脑在内的老年器官出现异常高的全身和粘膜炎症；2)功能障碍 肠道通透性(渗漏)和血脑屏障(BBB)；3)抑制自主神经(迷走神经)活动 与炎症增加有关；以及4)淀粉样β蛋白(Aβ)和牛磺酸蓄积增加。然而，没有 目前可用的药物针对与衰老相关的肠道和血脑屏障渗漏和/或迷走神经抑制，以减少 发炎。耐人寻味的是，二甲双胍(一种安全的临床批准药物，通常用于治疗糖尿病) 减少肠道和血脑屏障渗漏以及由此引起的炎症，从而减轻AD。这项研究建议是 旨在确定二甲双胍减少肠道和血脑屏障渗漏和/或迷走神经的机制 具有抑制炎症和AD进展的作用。我们对老年小鼠的初步研究证实 二甲双胍减少肠道渗漏和炎症，并调节肠道微生物区系以增加产量 丁酸盐是一种有益的微生物代谢物，也是健康微生物区系的指标。二甲双胍也有改善 老年和AD转基因(APP/PS1)患者的认知功能与脑内炎症和AD标志物的减少 老鼠。这些结果表明，二甲双胍调节肠-脑轴并减缓AD进展，但如何 二甲双胍导致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。 微生物区系抑制肠道渗漏和炎症，减缓AD进展。从机械上讲，我们 假设二甲双胍介导的肠炎症抑制是通过刺激迷走神经实现的 肠内神经和/或(Ii)减少血脑屏障渗漏，从而减少脑部炎症和AD进展。三 特定的目标验证了这一假设。在目标1中，确定二甲双胍修饰的肠道微生物区系是否是原因 对于其改善AD的效果，我们将移植经二甲双胍治疗的AD小鼠和对照AD小鼠的粪便微生物群 进入肠道清洁的APP/PS1小鼠(AD小鼠模型)，并评估肠道和脑部炎症的标志物，肠道 渗透性和AD进展。在目标2中，我们将评估二甲双胍引起的肠道变化是否涉及 (I)迷走神经和/或(Ii)血脑屏障通透性，以减少脑部炎症和AD进展。在《目标3》中，我们将 评估二甲双胍能否通过治疗成人和老年APP/PS1小鼠来延缓或治疗AD的病理 随着阿尔茨海默病的进展，使用二甲双胍。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进展的治疗方法。由NIH培训的新调查员领导，在 与尖端技术的多学科专家合作，这项研究适时地解决了RFA- AG-20-044(二甲双胍对衰老和长寿影响的生物学机制-R01，临床试验笔记 允许)。通过这项研究，我们将建立二甲双胍的生物学机制(S)，通过它可以成为潜在的 衰老相关AD的新疗法，这是老年人的一个令人衰弱的公共卫生问题。