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.

概括 衰老是阿尔茨海默病 (AD) 的一个主要危险因素，AD 的进展与 1) 相关。 老年器官（包括大脑）异常高的全身和粘膜炎症；2）功能障碍 肠道和血脑屏障 (BBB) 的渗透性（渗漏）；3) 抑制自主神经（迷走神经）活动； 与炎症增加有关；4) β 淀粉样蛋白 (Aβ) 和 Tau 蛋白积累增加，但没有。 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 有趣的是，二甲双胍（一种安全且经临床批准的药物，常用于治疗糖尿病）。 肠道减少 BBB 渗漏和随之而来的炎症，以减轻 AD。 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 我们对老年小鼠的初步研究证实了这一点。 二甲双胍可减少肠道渗漏和炎症，并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）的含量也有所改善。 老年人和 AD 转基因患者大脑中的认知功能以及炎症和 AD 标记物的减少 (APP/PS1) 这些结果表明二甲双胍可以调节肠-脑轴并减少 AD 的进展，但是它是如何调节的呢？ 二甲双胍导致这些变化尚不清楚，我们勇敢地说二甲双胍有益地调节肠道。 从机制上讲，我们通过微生物群来抑制肠道渗漏和炎症并减少 AD 进展。 二甲双胍介导的肠道炎症抑制是通过（i）刺激迷走神经介导的 肠道神经和/或 (ii) 减少 BBB 渗漏，从而减少大脑炎症和 AD 进展 三。 具体目标在目标 1 中检验这一假设，以确定二甲双胍修饰的肠道微生物群是否是因果关系。 为了了解其改善 AD 的效果，我们将移植二甲双胍治疗和对照 AD 小鼠的粪便微生物群 进入肠道净化的 APP/PS1 小鼠（AD 小鼠模型），并评估肠道和大脑炎症、肠道的标志物 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) BBB 通透性，以减少大脑炎症和 AD 进展 在目标 3 中，我们将。 评估二甲双胍是否可以通过治疗成年和老年 APP/PS1 小鼠来延缓或治疗 AD 的病理学 随着 AD 的进展，使用二甲双胍将建立概念验证并提供关键的临床前研究。 由 NIH 培训的新研究者领导的数据支持二甲双胍作为预防 AD 进展的疗法。 这项研究与尖端技术的多学科专家合作，及时解决了 RFA- AG-20-044（二甲双胍影响衰老和长寿的生物学机制 - R01，临床试验未 通过这项研究，我们将建立二甲双胍可能发挥作用的生物学机制。 与衰老相关的 AD 是一种令老年人衰弱的公共健康问题。