Role of MyD88 signaling in systemic inflammation and Alzheimer disease

MyD88 信号在全身炎症和阿尔茨海默病中的作用

基本信息

  • 批准号:
    10611489
  • 负责人:
  • 金额:
    $ 50.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-01 至 2026-04-30
  • 项目状态:
    未结题

项目摘要

Project Summary / Abstract The main pathological changes found in patients with Alzheimer’s disease (AD) are extracellular amyloid β (Aβ) deposits in the brain parenchyma (amyloid plaques) and abnormal aggregates of hyperphosphorylated tau protein in brain neurons (neurofibrillary tangles, NFTs). Amyloid plaques and NFTs are accompanied with chronic inflammation characterized by activated microglia and increased levels of cytokines. Except a small subset of early-onset familial AD cases, the causes for the vast majority of AD cases are unknown and satisfactory therapeutic and preventive measures for AD are unavailable. Therefore, an urgent need exists to identify the molecular mechanisms that increase the risk for the vast majority of AD cases and to develop the preventive and therapeutic measures. Systemic inflammation promotes AD progression and even initiates microglial activation and neurodegeneration. Indeed, recent genetic studies on late-onset AD have identified about a dozen genetic risk variants that are highly expressed in microglia and involved in innate immune responses, highlighting the importance of immune responses, particularly activated microglia, in the pathogenesis of late-onset AD. Aging is the largest known risk factor for AD and is characterized by chronic, systemic inflammation (inflamm-aging). Systemic inflammation caused by certain bacterial and viral infections is a strong risk factor of dementia, also. Additionally, our preliminary data indicate that activation of NLRP3 inflammasome through the MyD88 signaling pathway in microglia in the central nervous system (CNS) plays essential roles in the AD pathogenesis. In Aim 1, we will produce a microglia specific MyD88 deficiency in AD mouse models during aging and determine their effect on Aβ and tau pathology and cognitive function. We further hypothesize that microglial MyD88 signaling plays a predominant role in accelerating brain Aβ and tau pathology and neuroinflammation, which are induced by chronic, systemic inflammation, in AD mouse models during aging. In Aim 2, we will determine the effects of systemic LPS treatment on Aβ and tau pathology and cognition in AD mouse models with brain and peripheral immune cell-specific MyD88 deficiency. In Aim 3, we will determine the age and sex dependent effects of LPS treatment on NLRP3 inflammasome activation as disease mechanisms in the brain/microglia-specific and peripheral immune cell-specific MyD88 deficient AD mouse models. Our hypothesis is that LPS-induced systemic inflammation causes NLRP3 inflammasome activation in microglia via MyD88 signaling, leading to exacerbation of AD-like pathophysiology in AD mouse models. The long term goals are to determine the role of microglial MyD88/NLRP3 inflammasome signaling in the AD pathogenesis, to elucidate the molecular mechanism underlying the increased AD risk associated with systemic inflammation and to develop new preventive and therapeutic strategies for AD.
项目摘要/摘要

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A novel co-culture model for investigation of the effects of LPS-induced macrophage-derived cytokines on brain endothelial cells.
  • DOI:
    10.1371/journal.pone.0288497
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    3.7
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Ken-ichiro Fukuchi其他文献

Ken-ichiro Fukuchi的其他文献

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{{ truncateString('Ken-ichiro Fukuchi', 18)}}的其他基金

Role of MyD88 signaling in systemic inflammation and Alzheimer disease
MyD88 信号在全身炎症和阿尔茨海默病中的作用
  • 批准号:
    10456872
  • 财政年份:
    2021
  • 资助金额:
    $ 50.13万
  • 项目类别:
Role of MyD88 signaling in systemic inflammation and Alzheimer disease
MyD88 信号在全身炎症和阿尔茨海默病中的作用
  • 批准号:
    10314883
  • 财政年份:
    2021
  • 资助金额:
    $ 50.13万
  • 项目类别:
Altering immune tolerance in Alzheimer disease
改变阿尔茨海默病的免疫耐受性
  • 批准号:
    9979733
  • 财政年份:
    2019
  • 资助金额:
    $ 50.13万
  • 项目类别:
Role of extracellular vesicles in the high-fat diet-induced risk of Alzheimer disease
细胞外囊泡在高脂肪饮食诱发的阿尔茨海默病风险中的作用
  • 批准号:
    9385535
  • 财政年份:
    2017
  • 资助金额:
    $ 50.13万
  • 项目类别:
Role of diet-induced miR-34a in Alzheimer disease and dementia
饮食诱导的 miR-34a 在阿尔茨海默病和痴呆中的作用
  • 批准号:
    9225329
  • 财政年份:
    2017
  • 资助金额:
    $ 50.13万
  • 项目类别:
Role of the MyD88-independent pathway in Alzheimers disease
MyD88 独立通路在阿尔茨海默病中的作用
  • 批准号:
    8511261
  • 财政年份:
    2013
  • 资助金额:
    $ 50.13万
  • 项目类别:
Role of the MyD88-independent pathway in Alzheimers disease
MyD88 独立通路在阿尔茨海默病中的作用
  • 批准号:
    8676620
  • 财政年份:
    2013
  • 资助金额:
    $ 50.13万
  • 项目类别:
Catalytic and non-catalytic Ig gene delivery for Alzheimer's disease
阿尔茨海默病的催化和非催化 Ig 基因递送
  • 批准号:
    7963696
  • 财政年份:
    2010
  • 资助金额:
    $ 50.13万
  • 项目类别:
Catalytic and non-catalytic Ig gene delivery for Alzheimer's disease
阿尔茨海默病的催化和非催化 Ig 基因递送
  • 批准号:
    8081811
  • 财政年份:
    2010
  • 资助金额:
    $ 50.13万
  • 项目类别:
Innate immunity in Alzheimer's disease: Role of toll-like receptor signaling
阿尔茨海默氏病的先天免疫:Toll 样受体信号传导的作用
  • 批准号:
    7904117
  • 财政年份:
    2009
  • 资助金额:
    $ 50.13万
  • 项目类别:

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