Aged T-cell-derived cytokines impact meningeal lymphatics and contribute to AD

老化 T 细胞衍生的细胞因子影响脑膜淋巴管并导致 AD

基本信息

  • 批准号:
    10515246
  • 负责人:
  • 金额:
    $ 58.56万
  • 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:
    2022-08-17 至 2027-04-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Many age-related neurodegenerative diseases—including Alzheimer's disease (AD)—are associated with misfolded protein deposition that promote inflammatory responses, neuronal dysfunction, and cognitive deficits. We have recently identified that aging and AD both display impaired meningeal lymphatic function, which ultimately results in impaired CSF drainage to deep cervical lymph nodes, as well as CSF perfusion into the brain parenchyma, collectively promoting waste build up and A-induced pathologies in AD mice. Our preliminary data demonstrate that aging is also associated with the accumulation of IFNγ-producing CD4 and CD8 T cells in the dural meninges, closely associated with the meningeal lymphatics. IFNγ signaling represents a transcriptional hallmark of aged meningeal lymphatics and augmentation of this axis in young mice attenuates their functional drainage of CSF. We therefore hypothesize that during aging and in AD, elevated expression of IFNγ from meningeal CD4 and CD8 T cells impairs meningeal lymphatic function function via direct signaling on their IFNγ receptors, leading to meningeal lymphatic deterioration. Such deterioration later results in impaired brain perfusion by cerebrospinal fluid (CSF), subsequently leading to the accumulation of debris and worsening progression of AD. We further hypothesize that using cytokine neutralizing antibodies, we can preserve meningeal lymphatics in aged mice and prevent or reduce the age-associated brain dysfunctions and augment existing immunotherapy strategies in AD patients. Addressing our hypotheses of this proposal will illuminate mechanistic pathways underlying age-related meningeal lymphatic dysfunction, and identify new promising avenues for therapeutic interventions intended to reduce AD-related pathology.
项目总结

项目成果

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Jonathan Kipnis其他文献

Jonathan Kipnis的其他文献

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{{ truncateString('Jonathan Kipnis', 18)}}的其他基金

Neuroimmunology of AD and CAA with focus on innate immunity and lymphatics
AD 和 CAA 的神经免疫学,重点关注先天免疫和淋巴系统
  • 批准号:
    10674670
  • 财政年份:
    2022
  • 资助金额:
    $ 58.56万
  • 项目类别:
Aged T-cell-derived cytokines impact meningeal lymphatics and contribute to AD
老化 T 细胞衍生的细胞因子影响脑膜淋巴管并导致 AD
  • 批准号:
    10684836
  • 财政年份:
    2022
  • 资助金额:
    $ 58.56万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10674671
  • 财政年份:
    2022
  • 资助金额:
    $ 58.56万
  • 项目类别:
Parenchymal border macrophages in AD and CAA
AD 和 CAA 中的实质边界巨噬细胞
  • 批准号:
    10674673
  • 财政年份:
    2022
  • 资助金额:
    $ 58.56万
  • 项目类别:
Neural code of the immune responses
免疫反应的神经密码
  • 批准号:
    10223196
  • 财政年份:
    2018
  • 资助金额:
    $ 58.56万
  • 项目类别:
Neural code of the immune responses
免疫反应的神经密码
  • 批准号:
    9788254
  • 财政年份:
    2018
  • 资助金额:
    $ 58.56万
  • 项目类别:
Neural code of the immune responses
免疫反应的神经密码
  • 批准号:
    10218743
  • 财政年份:
    2018
  • 资助金额:
    $ 58.56万
  • 项目类别:
Neural code of the immune responses
免疫反应的神经密码
  • 批准号:
    10457300
  • 财政年份:
    2018
  • 资助金额:
    $ 58.56万
  • 项目类别:
Meningeal lymphatics and immunity in Alzheimer's disease
阿尔茨海默病的脑膜淋巴管和免疫
  • 批准号:
    9428316
  • 财政年份:
    2017
  • 资助金额:
    $ 58.56万
  • 项目类别:
Immune response to CNS injury
对中枢神经系统损伤的免疫反应
  • 批准号:
    9241450
  • 财政年份:
    2016
  • 资助金额:
    $ 58.56万
  • 项目类别:

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