New role(s) for IRF5 as a regulator of tau accumulation in Alzheimer’s disease

IRF5 在阿尔茨海默病中调节 tau 蛋白积累的新作用

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT Tau pathology is central to the development of Alzheimer’s disease (AD) and its clinical progression, hence current therapeutic efforts are directed at reducing tau burden in the brain by immunotherapy. The initial seeding and deposition of tau is associated with an early inflammatory response, in both human disease and mouse models of AD. The immune system responds rapidly to the accumulation of tau and other aggregated proteins, in order to clear them from the brain and prevent further immune activation. However, if clearance is unsuccessful, the accumulation of aggregated proteins will likely lead to excessive inflammation, and paradoxically, more tau spreading and accumulation. This complex relationship between tau pathology and inflammation is still not fully characterized. We identified the transcription factor interferon regulatory factor 5 (IRF5) as a new mediator of microglia activation in response to pathological tau. We found that IRF5 is activated, i.e. nuclear-localized, in microglia after stimulation with pathological tau, and IRF5 expression is increased in brain tissue from AD patients as compared to healthy donors. Further, aged mice lacking IRF5 showed increased accumulation of soluble tau. Together, these data suggest a new role for IRF5 in microglia immunosurveillance of aggregated, pathological tau. The premise of this application is that IRF5-mediated signaling in microglia is a critical step in regulating tau accumulation. In this proposal, we will 1) Test the hypothesis that IRF5 is required for immunosurveillance of pathological tau in the brain, 2) Determine whether therapeutic inhibition of IRF5 protects P301S mice from disease onset, progression and neurodegeneration, and 3) Determine the mechanism(s) by which IRF5 participates in the immune response against pathological tau. Successful completion of these studies will 1) identify a new factor – IRF5 – that contributes to immunosurveillance of pathogenic stimuli in the brain and 2) determine whether IRF5 is a viable therapeutic target for AD and tauopathies.
项目总结/文摘

项目成果

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Betsy J Barnes其他文献

Betsy J Barnes的其他文献

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{{ truncateString('Betsy J Barnes', 18)}}的其他基金

Implications for Speckled proteins 110 and 140 in adaptive immunity
斑点蛋白 110 和 140 对适应性免疫的影响
  • 批准号:
    10726020
  • 财政年份:
    2023
  • 资助金额:
    $ 25.13万
  • 项目类别:
Investigating monocyte dysfunction in Down Syndrome
研究唐氏综合症的单核细胞功能障碍
  • 批准号:
    10854106
  • 财政年份:
    2019
  • 资助金额:
    $ 25.13万
  • 项目类别:
IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis
系统性幼年特发性关节炎中的 IRF5 和巨噬细胞激活综合征
  • 批准号:
    10199939
  • 财政年份:
    2019
  • 资助金额:
    $ 25.13万
  • 项目类别:
IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis
系统性幼年特发性关节炎中的 IRF5 和巨噬细胞激活综合征
  • 批准号:
    10454915
  • 财政年份:
    2019
  • 资助金额:
    $ 25.13万
  • 项目类别:
IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis
系统性幼年特发性关节炎中的 IRF5 和巨噬细胞激活综合征
  • 批准号:
    9982787
  • 财政年份:
    2019
  • 资助金额:
    $ 25.13万
  • 项目类别:
IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis
系统性幼年特发性关节炎中的 IRF5 和巨噬细胞激活综合征
  • 批准号:
    10663266
  • 财政年份:
    2019
  • 资助金额:
    $ 25.13万
  • 项目类别:
Determining the function of IRF5 tumor suppressor in HCV pathogenesis
确定 IRF5 抑癌基因在 HCV 发病机制中的功能
  • 批准号:
    9108325
  • 财政年份:
    2015
  • 资助金额:
    $ 25.13万
  • 项目类别:
Determining the function of IRF5 tumor suppressor in HCV pathogenesis
确定 IRF5 抑癌基因在 HCV 发病机制中的功能
  • 批准号:
    9147052
  • 财政年份:
    2015
  • 资助金额:
    $ 25.13万
  • 项目类别:
IRF5-TNPO3 locus: Inclusion of TNPO3 as a unique regulator of IRF5 expression an
IRF5-TNPO3 基因座:将 TNPO3 作为 IRF5 表达的独特调节因子纳入其中
  • 批准号:
    8664081
  • 财政年份:
    2014
  • 资助金额:
    $ 25.13万
  • 项目类别:
IRF5-TNPO3 locus: Inclusion of TNPO3 as a unique regulator of IRF5 expression an
IRF5-TNPO3 基因座:将 TNPO3 作为 IRF5 表达的独特调节因子纳入其中
  • 批准号:
    9220283
  • 财政年份:
    2014
  • 资助金额:
    $ 25.13万
  • 项目类别:
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