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

基本信息

  • 批准号:
    10228313
  • 负责人:
  • 金额:
    $ 9.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

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Hariom Yadav其他文献

Hariom Yadav的其他文献

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{{ truncateString('Hariom Yadav', 18)}}的其他基金

Microbial therapy improves gut permeability to reduce cognitive decline and Alzheimer’s disease
微生物疗法可改善肠道通透性,从而减少认知能力下降和阿尔茨海默病
  • 批准号:
    10185582
  • 财政年份:
    2021
  • 资助金额:
    $ 9.31万
  • 项目类别:
The role of gut microbiota in the efficacy of ketogenic diet to ameliorate Alzheimer's disease
肠道微生物群在生酮饮食改善阿尔茨海默病功效中的作用
  • 批准号:
    10196134
  • 财政年份:
    2021
  • 资助金额:
    $ 9.31万
  • 项目类别:
Gut microbiota-based biomarkers of Alzheimer's disease and its modulation by a ketogenic diet
基于肠道微生物群的阿尔茨海默病生物标志物及其生酮饮食的调节
  • 批准号:
    10461652
  • 财政年份:
    2020
  • 资助金额:
    $ 9.31万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 9.31万
  • 项目类别:
Gut microbiota-based biomarkers of Alzheimer's disease and its modulation by a ketogenic diet
基于肠道微生物群的阿尔茨海默病生物标志物及其生酮饮食的调节
  • 批准号:
    10247241
  • 财政年份:
    2020
  • 资助金额:
    $ 9.31万
  • 项目类别:

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