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

批准号：
10098370
负责人：
Clarissa Leigh Waites
金额：
$ 232.55万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10098370
关键词：
Address Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer’s disease biomarker American Amyloid beta-Protein Anatomy Animals Astrocytes Atrophic Biochemistry Biological Biological Markers Blood Brain Brain Pathology Brain region Cause of Death Cells Chronic Chronic stress Clinical Research Complex Defect Degradation Pathway Dementia Diagnosis Disease Disease Progression Down-Regulation Early Diagnosis Early treatment Environmental Risk Factor Exhibits Exposure to Functional disorder Gene Expression Profiling Genetic Risk Genetic Transcription Glucocorticoid Receptor Glucocorticoids Hippocampus (Brain)Hormones Image Immune Immunofluorescence Microscopy Impairment Injections Knockout Mice Label Lead Learning Link MAPT gene Mediating Mediator of activation protein Memory Memory impairment MicroRNAs Microglia Molecular Monitor Mus Neocortex Neuroglia Neurons Pathogenesis Pathology Plasma Process Property Proteins Proteomics Psychological Stress Publishing Regulation Risk Risk Factors Role Sex Differences Stress Tauopathies Testing Tissues United States Vertebral column Vesicle Wild Type Mouse Work brain dysfunction brain tissue cell type conditional knockout density effective therapy entorhinal cortex epidemiology study exosome experimental study extracellular vesicles hippocampal atrophy human old age (65+)in vivo innovation intercellular communication mouse model nanoparticle neurotoxicity new therapeutic target potential biomarker prevent reuptake sex tau Proteins tau aggregation tau expression tau mutation therapy development transcriptome uptake

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) 是最常见的痴呆症，是美国的主要原因。临床和流行病学研究表明，慢性心理压力和糖皮质激素水平升高 (GC) 是主要的应激激素，与 AD 风险增加有关，但与 AD 风险增加相关的因素却很少。我们最近的工作表明，压力如何引发或恶化 AD 病理机制。应激/GC 诱导 Tau 积累和过度磷酸化，以及 Tau 依赖性海马萎缩此外，应激性 AD 小鼠模型似乎表现出刻板的传播。解剖学上相连的大脑区域之间的 Tau 病理学，类似于在 AD 患者大脑中观察到的情况。这种传播是通过致病性 Tau 物种的神经元分泌而发生的，可能涉及外泌体是介导细胞间通讯的分泌囊泡，这些发现表明 Tau 蛋白是一种关键蛋白。然而，将压力/GC 与 Tau 联系起来的潜在机制。同样，人们对发病机制仍知之甚少，用于检测/监测的生物标志物也很少。压力相关的大脑病理学，可以促进 AD 的早期诊断和治疗。在跨学科提案中，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 Tau 积累和分泌的机制，我们将使用细胞生物学方法。研究 GC 诱导的降解途径功能障碍、Tau 聚集和同时，我们将进行细胞类型特异性基因表达。对糖皮质激素受体 (GR) 条件敲除小鼠进行分析，以确定压力如何调节海马神经元、星形胶质细胞和小胶质细胞的转录组促进 Tau 病理学在目标 2 中，我们将进行研究。研究压力如何介导体内 Tau 病理学的传播。在这里，我们将评估 Tau 蛋白病理学的能力。慢性应激刺激 Tau 增殖和 Tau 病理学的扩散，外泌体的作用在目标 3 中，我们将评估外泌体在压力驱动下的生物标志物潜力。在这里，我们将从野生型小鼠和三种 AD/tau 病的血液和大脑中分离出外泌体。暴露于对照或应激条件后的小鼠模型将用于进行蛋白质组学和 microRNA 分析。比较它们的含量并识别受压力上调/下调的蛋白质和 microRNA。实验将揭示是否存在可以在不同性别的外泌体中检测到的强有力的压力标记物，总体而言，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 诊断和治疗带来新的治疗靶点和生物标志物。