Uncovering stress-induced mechanisms of Tau pathology in Alzheimer's disease

揭示阿尔茨海默病中压力诱导的 Tau 病理机制

基本信息

项目摘要

Alzheimer’s disease (AD), the most common form of dementia, is a leading cause of death in the United States. Clinical and epidemiological studies show that chronic psychological stress and elevated levels of glucocorticoids (GCs), the major stress hormones, are associated with increased risk of developing AD. However, very little is known about how stress triggers or exacerbates AD pathomechanisms. Our recent work has shown that chronic stress/GCs induce Tau accumulation and hyperphosphorylation, as well as Tau-dependent hippocampal atrophy and learning/memory deficits. Moreover, stressed AD mouse models appear to show a stereotypical spreading of Tau pathology between anatomically connected brain regions, similar to what is observed in AD patient brains. Such spreading occurs via neuronal secretion of pathogenic Tau species, with the potential involvement of exosomes, secreted vesicles that mediate intercellular communication. These findings implicate Tau as a critical mediator of stress-induced brain pathology. However, the underlying mechanisms linking stress/GCs to Tau pathogenesis remain poorly understood. Similarly, there are few if any biomarkers for detecting/monitoring stress-related brain pathology, which could facilitate earlier diagnosis and treatment of AD. In this innovative and interdisciplinary proposal, we will address these issues. In Aim 1, we will elucidate the cellular and molecular mechanisms of stress/GC-induced Tau accumulation and secretion. Using cell biological approaches, we will investigate the relationship between GC-induced degradative pathway dysfunction, Tau aggregation, and Tau/exosome secretion in neurons and glia. In parallel, we will perform cell type-specific gene expression profiling in glucocorticoid receptor (GR) conditional knockout mice to determine how stress regulates the transcriptomes of hippocampal neurons, astrocytes, and microglia to promote Tau pathology. In Aim 2, we will investigate how stress mediates the propagation of Tau pathology in vivo. Here, we will assess the ability of chronic stress to stimulate Tau propagation and the spreading of Tau pathology, focusing the roles of exosomes and microglia in this process. In Aim 3, we will evaluate the biomarker potential of exosomes in stress-driven brain pathology. Here, we will isolate exosomes from blood and brains of wild-type mice and three AD/tauopathy mouse models after exposure to control or stress conditions. Proteomics and microRNA profiling will be used to compare their contents and identify proteins and microRNAs that are up/downregulated by stress. These experiments will reveal whether there are robust markers of stress that can be detected in exosomes across sex, AD model, and tissue type. Overall, these studies will illuminate cellular mechanisms by which stress/GCs induce Tau-related neurotoxicity, and lead to novel therapeutic targets and biomarkers for AD diagnosis and treatment.
阿尔茨海默病(AD)是痴呆症的最常见形式,是美国的主要死亡原因。 临床和流行病学研究表明,慢性心理应激和糖皮质激素水平升高 (GCs),主要的应激激素,与患AD的风险增加有关。然而,很少有 了解压力如何触发或加剧AD病理机制。我们最近的研究表明, 应激/GC诱导Tau积累和过度磷酸化以及Tau依赖性海马萎缩 和学习记忆缺陷此外,应激AD小鼠模型似乎显示出刻板的传播, 在解剖学上连接的脑区域之间的Tau病理学,类似于在AD患者脑中观察到的。 这种扩散通过致病性Tau种类的神经元分泌发生,其中可能涉及 外泌体,介导细胞间通讯的分泌囊泡。这些发现暗示Tau是一个关键的 压力诱导的大脑病理学的介质。然而,将压力/GC与Tau联系起来的潜在机制 发病机制仍然知之甚少。类似地,用于检测/监测的生物标志物(如果有的话)很少。 应激相关的脑病理学,这可能有助于早期诊断和治疗AD。在这一创新和 跨学科的建议,我们将解决这些问题。在目标1中,我们将阐明细胞和分子 应激/GC诱导的Tau积累和分泌的机制。使用细胞生物学方法,我们将 研究GC诱导的降解途径功能障碍、Tau聚集和 神经元和神经胶质中的Tau/外泌体分泌。同时,我们将进行细胞类型特异性基因表达 在糖皮质激素受体(GR)条件性敲除小鼠中进行分析,以确定应激如何调节 在一些实施方案中,本发明涉及海马神经元、星形胶质细胞和小胶质细胞的转录组以促进Tau病理。在目标2中,我们 研究应激如何在体内介导Tau病理学的传播。在这里,我们将评估 慢性应激刺激Tau增殖和Tau病理学的传播,聚焦外泌体的作用 和小胶质细胞参与其中在目标3中,我们将评估外泌体在应激驱动的细胞中的生物标志物潜力。 脑病理学在这里,我们将从野生型小鼠和三种AD/tau蛋白病小鼠的血液和脑中分离外泌体。 暴露于对照或应激条件后的小鼠模型。蛋白质组学和microRNA分析将用于 比较它们的含量,并确定蛋白质和微RNA,是向上/向下调节的压力。这些 实验将揭示是否有强大的压力标记物可以在不同性别的外来体中检测到, AD模型和组织类型。总之,这些研究将阐明应激/GC诱导的细胞机制。 Tau相关的神经毒性,并为AD的诊断和治疗带来新的治疗靶点和生物标志物。

项目成果

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Clarissa Leigh Waites其他文献

Clarissa Leigh Waites的其他文献

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{{ truncateString('Clarissa Leigh Waites', 18)}}的其他基金

Uncovering the roles of ubiquitination and the ESCRT pathway in degradative sorting of SV proteins.
揭示泛素化和 ESCRT 通路在 SV 蛋白降解分选中的作用。
  • 批准号:
    10162269
  • 财政年份:
    2020
  • 资助金额:
    $ 232.55万
  • 项目类别:
High-throughput screening platform for discovery of fluorescent synaptic markers
用于发现荧光突触标记的高通量筛选平台
  • 批准号:
    8769206
  • 财政年份:
    2014
  • 资助金额:
    $ 232.55万
  • 项目类别:
Uncovering the Roles of Ubiquitination and the ESCRT Pathway in Degradative Sorting of SV Proteins.
揭示泛素化和 ESCRT 途径在 SV 蛋白降解分选中的作用。
  • 批准号:
    10576875
  • 财政年份:
    2014
  • 资助金额:
    $ 232.55万
  • 项目类别:
Uncovering the roles of ubiquitination and the ESCRT pathway in degradative sorting of SV proteins.
揭示泛素化和 ESCRT 通路在 SV 蛋白降解分选中的作用。
  • 批准号:
    10364729
  • 财政年份:
    2014
  • 资助金额:
    $ 232.55万
  • 项目类别:
Elucidating a molecular pathway for synaptic vesicle maintenance and degradation
阐明突触小泡维持和降解的分子途径
  • 批准号:
    8765805
  • 财政年份:
    2014
  • 资助金额:
    $ 232.55万
  • 项目类别:
High-throughput screening platform for discovery of fluorescent synaptic markers
用于发现荧光突触标记的高通量筛选平台
  • 批准号:
    8910791
  • 财政年份:
    2014
  • 资助金额:
    $ 232.55万
  • 项目类别:
Elucidating a molecular pathway for synaptic vesicle maintenance and degradation
阐明突触小泡维持和降解的分子途径
  • 批准号:
    8578781
  • 财政年份:
    2013
  • 资助金额:
    $ 232.55万
  • 项目类别:
Elucidating a molecular pathway for synaptic vesicle maintenance and degradation
阐明突触小泡维持和降解的分子途径
  • 批准号:
    8672702
  • 财政年份:
    2013
  • 资助金额:
    $ 232.55万
  • 项目类别:
Elucidating a molecular pathway for synaptic vesicle maintenance and degradation
阐明突触小泡维持和降解的分子途径
  • 批准号:
    8899649
  • 财政年份:
    2013
  • 资助金额:
    $ 232.55万
  • 项目类别:
The role of dense core vesicles in synapse formation
致密核心囊泡在突触形成中的作用
  • 批准号:
    6893692
  • 财政年份:
    2003
  • 资助金额:
    $ 232.55万
  • 项目类别:
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