Cellular senescence, inflammation and neurotransmission in Alzheimer's disease

阿尔茨海默病中的细胞衰老、炎症和神经传递

基本信息

  • 批准号:
    10198750
  • 负责人:
  • 金额:
    $ 66.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-30 至 2023-05-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Alzheimer’s disease (AD) lies on a continuum with dynamic neurobiological and pathological symptoms / markers, therefore we need to identify novel biomarkers to optimize targeted therapies for improved patient care. Increasing evidence support that age-related accumulation of senescent cells, chronic inflammation, and altered glutamate neurotransmission represent inter-related mechanisms that increase the risk for developing AD. Understanding this interaction is crucial to identifying novel therapeutic targets for improving patient outcome. Existing data support the proteinopathy-induced senescent cell hypothesis of AD proposed by Golde and Miller, whereby soluble and insoluble Aβ activates the innate immune system triggering a self-reinforcing cycle of pro-inflammatory signaling and cellular senescence, ultimately leading to neurodegeneration (possibly through altered glutamate neurotransmission), and cognitive decline in AD. However, the role of Aβ42 and glutamate neurotransmission in this self-reinforcing cycle, and whether decreasing cellular senescence and / or inflammation can prevent cognitive decline, is unknown. Addressing this gap in knowledge may be key to identifying underlying mechanisms and therapeutics that have the ability to alter functional outcomes. To address our central hypothesis that reducing the burden of senescent cells and shifting the profile of adipokines and cytokines from pro- to anti-inflammatory will restore glutamate neurotransmission and thereby slow or prevent AD-related cognitive decline, we will target cellular senescence (Aim 1) or systemic inflammation (Aim 2) at two distinct time points during disease progression; 1) 4-5 months of age, elevated soluble Aβ42, some plaque buildup, and little to no cognitive decline, and 2) 16-17 months of age, significant plaques accumulation and cognitive decline. This will allow us to examine both the long term and short term effects of these interventions. The studies will help determine the mechanisms by which brain aging and Aβ42 impacts the development and progression of AD and may lead to interventions through identification of novel, disease stage specific biomarkers and optimal therapeutic treatment windows.
项目总结/文摘

项目成果

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Erin R Hascup其他文献

Erin R Hascup的其他文献

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{{ truncateString('Erin R Hascup', 18)}}的其他基金

Cellular senescence, inflammation and neurotransmission in Alzheimer's disease
阿尔茨海默病中的细胞衰老、炎症和神经传递
  • 批准号:
    9788263
  • 财政年份:
    2018
  • 资助金额:
    $ 66.88万
  • 项目类别:
Cellular senescence, inflammation and neurotransmission in Alzheimer's disease
阿尔茨海默病中的细胞衰老、炎症和神经传递
  • 批准号:
    10450727
  • 财政年份:
    2018
  • 资助金额:
    $ 66.88万
  • 项目类别:
Glutamate neurotransmission in Alzheimer's disease progression
阿尔茨海默病进展中的谷氨酸神经传递
  • 批准号:
    10398111
  • 财政年份:
    2018
  • 资助金额:
    $ 66.88万
  • 项目类别:
Glutamate neurotransmission in Alzheimer's disease progression
阿尔茨海默病进展中的谷氨酸神经传递
  • 批准号:
    9906833
  • 财政年份:
    2018
  • 资助金额:
    $ 66.88万
  • 项目类别:
Research Supplement to Promote Diversity for R01AG061937
促进 R01AG061937 多样性的研究补充
  • 批准号:
    9924186
  • 财政年份:
    2018
  • 资助金额:
    $ 66.88万
  • 项目类别:
Equipment request to increase scientific rigor and reproducibility
提高科学严谨性和可重复性的设备要求
  • 批准号:
    10060295
  • 财政年份:
    2018
  • 资助金额:
    $ 66.88万
  • 项目类别:

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