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

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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.