Mitochondrial dysfunction and tau pathology in Alzheimer's disease

阿尔茨海默病中的线粒体功能障碍和 tau 病理学

基本信息

  • 批准号:
    10805120
  • 负责人:
  • 金额:
    $ 42.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-16 至 2025-09-15
  • 项目状态:
    未结题

项目摘要

Alzheimer’s disease (AD) is the most common cause of dementia with no current interventions that halt or substantially slow disease progression. AD is a multifactorial disease characterized by impaired mitochondrial bioenergetics, oxidative stress, and tau pathology. These AD pathologies are interconnected, change over time, and correlate with neuronal dysfunction. Moreover, the hallmarks are dynamic and difficult to isolate experimentally, which makes assigning causation challenging and limits therapeutic development. This proposal uses novel optogenetic technology developed for hypoxic biology to address this gap and test if mitochondrial dysfunction and reactive oxygen species (ROS) production are causal for the progression of tau pathology. Our approach involves directly controlling mitochondrial function and ROS production using light, without interfering with metabolism or using irreversible toxins with off-target effects. The optogenetic tools mitochondria-ON (mtON) and mitochondria-OFF (mtOFF) are mitochondria-targeted light-activated proton pumps that alter mitochondrial bioenergetics to turn ‘on’ or ‘off’ mitochondrial function in response to light. Similarly, mtSuperNova is a mitochondria-targeted genetically-encoded photosensitizer which generates ROS in response to light. These tools will spatiotemporally control mitochondrial function and ROS production in both an ex vivo brain slice culture and an in vivo mouse model using the PS19 mouse line (P301S tau). These mice exhibit early mitochondrial dysfunction and have been used extensively to study tau pathology and are an optimal model for these studies. Organotypic brain slice cultures will be used to provide a three-dimensional system to mechanistically test when and how mitochondrial energetics and ROS production contribute to pathological tau modifications. AD is largely associated with aging; therefore, in we will bridge our ex vivo findings into an adult in vivo model. Using a wireless optogenetic system, we will illuminate hippocampi in live, freely moving PS19 adult mice to test the effect of mitochondrial dysfunction over time on measures of oxidative stress and tau pathology. Mitochondrial dysfunction and ROS production have long been associated with AD pathology however the cause-and-effect relationship is unclear. Our novel technology provides an approach to directly test the role of mitochondria in AD independent of confounding factors. Overall, these studies will begin to clearly define the role of mitochondria in the evolution of tau pathology and provide mechanistic insights into therapeutic opportunities to attenuate AD pathogenesis.
阿尔茨海默病(AD)是痴呆症的最常见原因,目前没有干预措施可以阻止或阻止

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Gail V. W. Johnson其他文献

Glycogen Synthase Kinase 3β Phosphorylates Tau at Both Primed and Unprimed Sites
糖原合酶激酶 3β 在引发和未引发的位点磷酸化 Tau
Metal-catalyzed oxidation of bovine neurofilaments in vitro.
牛神经丝的体外金属催化氧化。
  • DOI:
  • 发表时间:
    1995
  • 期刊:
  • 影响因子:
    7.4
  • 作者:
    Juan C. Troncoso;Anthony C. Costello;James H. Kim;Gail V. W. Johnson
  • 通讯作者:
    Gail V. W. Johnson

Gail V. W. Johnson的其他文献

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{{ truncateString('Gail V. W. Johnson', 18)}}的其他基金

Mechanisms of Transglutaminase 2 (TG2)-Mediated Gene Expression in Astrocyte
星形胶质细胞中转谷氨酰胺酶 2 (TG2) 介导的基因表达机制
  • 批准号:
    10293984
  • 财政年份:
    2021
  • 资助金额:
    $ 42.35万
  • 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
  • 批准号:
    10269305
  • 财政年份:
    2021
  • 资助金额:
    $ 42.35万
  • 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
  • 批准号:
    10461933
  • 财政年份:
    2021
  • 资助金额:
    $ 42.35万
  • 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
  • 批准号:
    10667539
  • 财政年份:
    2021
  • 资助金额:
    $ 42.35万
  • 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
  • 批准号:
    10374933
  • 财政年份:
    2020
  • 资助金额:
    $ 42.35万
  • 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
  • 批准号:
    10188394
  • 财政年份:
    2020
  • 资助金额:
    $ 42.35万
  • 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
  • 批准号:
    10601125
  • 财政年份:
    2020
  • 资助金额:
    $ 42.35万
  • 项目类别:
Tau protein turnover and mitochondrial stress responses
Tau 蛋白周转和线粒体应激反应
  • 批准号:
    9761421
  • 财政年份:
    2018
  • 资助金额:
    $ 42.35万
  • 项目类别:
The degradation of tau by selective autophagy
选择性自噬降解 tau
  • 批准号:
    9395850
  • 财政年份:
    2017
  • 资助金额:
    $ 42.35万
  • 项目类别:
The degradation of tau by selective autophagy
选择性自噬降解 tau
  • 批准号:
    9918995
  • 财政年份:
    2017
  • 资助金额:
    $ 42.35万
  • 项目类别:

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新型 PPAR-gamma 激动剂选择性激活 PPAR-gamma 的配体结合域,改善 3xTg-Ad 小鼠模型的病理和记忆缺陷。
  • 批准号:
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