Microbial dysbiosis as a driver of neuroinflammation and pathology in Alzheimer's disease

微生物失调是阿尔茨海默病神经炎症和病理的驱动因素

基本信息

  • 批准号:
    10370667
  • 负责人:
  • 金额:
    $ 43.47万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-02-15 至 2024-01-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Recent advances have helped to uncover critical roles for gut microbiota in a spectrum of neurological disorders including many neurodegenerative diseases. In the case of Alzheimer’s disease (AD), it has been shown in both AD patients and animal models that neurodegenerative disease progression is associated with large-scale changes in gut microbiota composition. Moreover, recent data also suggest that ablation of the microbiome with either germ-free re-derivation or chronic treatment with broad-spectrum antibiotics water limits amyloidosis in mice that over-express amyloid beta (Ab). While these findings have led to excitement over the potential role for microbial dysbiosis in AD, numerous fundamental questions still remain to be answered on this topic. For one, all of these previous studies have only explored the impact of the murine microbiome on neurodegenerative disease and have not investigated how the specific dysbiosis seen in AD patients affects neurological disease progression. Given the major differences that exist between the mouse and human microbiome, it will be important to specifically probe how alterations in human gut microbiota influence neurodegenerative disease processes. In addition, little is currently known regarding how microbial dysbiosis affects tauopathy. To fill these gaps in knowledge, we will transplant gut microbiota from either AD patients or age- and sex-matched controls into germ-free 3xTg-AD mice, which is a well-described mouse model of AD that develops age-related and progressive Ab-induced neurological disease and tauopathy. The impact of human AD-associated dysbiosis on disease progression will then be determined by evaluating Ab deposition, tauopathy, neurodegeneration, neuroinflammation, and cognitive performance (Aim 1). Recent studies in other non-AD models of neurodegenerative disease suggest that the gut microbiota can influence disease progression via modulation of the immune system and/or by promoting changes in metabolite generation. Therefore, in our second Aim, we will next leverage cutting-edge single-cell RNA-sequencing (scRNA-seq) and metabolomics approaches to provide a comprehensive and unbiased assessment of how AD-associated dysbiosis affects immune responses and the metabolome in our human microbiota transplantation AD mouse model. Our overarching hypothesis is that microbial dysbiosis in AD patients leads to exacerbated neurodegenerative disease progression and that this is associated with dysregulation of immune responses and the metabolome. Successful completion of these proposed research directions will break new ground in our understanding of the role of AD-associated dysbiosis in neurodegenerative disease pathogenesis and will also begin to reveal prospective factors underpinning the effects of the human AD microbiome on disease progression. Furthermore, findings from these studies are of potential translational significance as they could help to establish the microbiome as a therapeutic target to pursue in the treatment of AD.
摘要

项目成果

期刊论文数量(0)
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John R Lukens其他文献

Harnessing microglia-based cell therapies for the treatment of neurodegenerative diseases
利用基于小胶质细胞的细胞疗法治疗神经退行性疾病
  • DOI:
    10.1016/j.coi.2025.102552
  • 发表时间:
    2025-06-01
  • 期刊:
  • 影响因子:
    5.800
  • 作者:
    Adeline E Walsh;John R Lukens
  • 通讯作者:
    John R Lukens

John R Lukens的其他文献

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{{ truncateString('John R Lukens', 18)}}的其他基金

CLEC7A in microglia biology and Alzheimer's disease
CLEC7A 在小胶质细胞生物学和阿尔茨海默病中的作用
  • 批准号:
    10659940
  • 财政年份:
    2023
  • 资助金额:
    $ 43.47万
  • 项目类别:
Role of the SYK-CARD9 signaling axis in Alzheimer's disease
SYK-CARD9 信号轴在阿尔茨海默病中的作用
  • 批准号:
    10198453
  • 财政年份:
    2021
  • 资助金额:
    $ 43.47万
  • 项目类别:
Delineating the effects of sex on microglia in neurodevelopmental disorders
描述性别对神经发育障碍中小胶质细胞的影响
  • 批准号:
    9809266
  • 财政年份:
    2019
  • 资助金额:
    $ 43.47万
  • 项目类别:
Inflammasome activation and lymphatic dysfunction in traumatic brain injury
创伤性脑损伤中的炎症小体激活和淋巴功能障碍
  • 批准号:
    10459460
  • 财政年份:
    2018
  • 资助金额:
    $ 43.47万
  • 项目类别:
Inflammasome activation and lymphatic dysfunction in traumatic brain injury
创伤性脑损伤中的炎症小体激活和淋巴功能障碍
  • 批准号:
    10222790
  • 财政年份:
    2018
  • 资助金额:
    $ 43.47万
  • 项目类别:
Inflammasome activation and lymphatic dysfunction in traumatic brain injury
创伤性脑损伤中的炎症小体激活和淋巴功能障碍
  • 批准号:
    9977266
  • 财政年份:
    2018
  • 资助金额:
    $ 43.47万
  • 项目类别:

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