Deciphering tau phosphorylation and Abeta/tau strain interactions in Alzheimer’s pathogenesis

破译阿尔茨海默病发病机制中的 tau 磷酸化和 Abeta/tau 菌株相互作用

• 批准号: 10709892
• 负责人: DAVID R BORCHELT
• 金额: $ 49.03万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709892
• 关键词: Abeta synthesis; Age; Age Months; Aging; Alanine; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Antibodies; Aspartic Acid; Automobile Driving; Brain; Characteristics; Clinical; Cognitive deficits; Collection; Data; Data Analyses; Dementia; Deposition; Diffuse; Early Onset Familial Alzheimer' s Disease; Elderly; Environment; Epitopes; Etiology; Event; Exhibits; Goals; Harvest; Hippocampus; Human; Individual; Injections; Knowledge; Laboratories; Late Onset Alzheimer Disease; Link; Maps; Mediating; Modeling; Mus; Mutate; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Newborn Infant; Outcome; Pathogenesis; Pathologic; Pathology; Phosphorylation; Phosphorylation Site; Process; Recombinant adeno-associated virus (rAAV); Research; Role; Secondary to; Senile Plaques; Severities; Site; Symptoms; Tauopathies; Technology; Tetracyclines; Transgenic Mice; Transgenic Model; Variant; Virus; Work; abeta deposition; adeno-associated viral vector; amyloid pathology; beta amyloid pathology; design; extracellular; histological stains; hyperphosphorylated tau; improved; insight; mimetics; mouse model; neurofibrillary tangle formation; neuropathology; pharmacologic; phosphoproteomics; synergism; tau Proteins; tau aggregation; tau expression; tau interaction; tau mutation; tau-1; β-amyloid burden

Abstract The clinical symptoms of Alzheimer disease (AD) dementia occur downstream of pathological deposition of Aβ peptides in extracellular cored-neuritic plaques and aggregated tau protein in intracellular neurofibrillary tangles (NFT) in the brain. Since deposition of Aβ precedes tauopathy in early-onset familial AD (fAD), it is accepted that Aβ can trigger tau misfolding into NFT, initiating a cascade of cumulative pathology that progressively leads to dementia. In sporadic AD, the coincident deposition of Aβ appears to correlate with tau misfolding and the severity of NFT pathology. Collectively, these findings suggest that Aβ deposition can exacerbate tau misfolding and NFT formation leading to cognitive deficits and dementia. However, the underlying mechanisms and characteristics of Aβ and tau that synergize resulting in NFT pathology and pathological sequelae is still unclear. Our proposal is designed to provide experimental insights into the individual contribution of tau (Aim 1) and Aβ (Aim 2) in driving Aβ-tau synergy in mouse models of AD. Evidence suggests that a major mechanism by which Aβ synergizes with tau misfolding involves the hyper-phosphorylation of tau. A recent study of AD patients that quantitatively mapped the progressive emergence of phosphorylated epitopes in tau identified 19 Ser/Thr residues that are most frequently phosphorylated in individuals that exhibit concurrent Aβ pathology. The main objective in Aim 1 is to dissect the contribution of these phosphorylation events in the misfolding and aggregation of tau that occurs in the presence of concurrent Aβ pathology. Using AAV technology, we have the capability to generate and express a large number of tau phospho-mimetic variants in APP TgCRND8 mice. Using this mouse model, in Aim 1 we propose a broad study to systematically dissect the phosphorylation events that drive tau misfolding and NFT formation in the presence of Aβ. Over many years of research, our laboratories have created mouse models that exhibit a spectrum of Aβ pathologies, including mice that develop primarily diffuse Aβ pathology and mice that primarily develop cored- neuritic pathology. Given that there are questions regarding the type of Aβ pathology that underlie Aβ-tau synergy, in Aim 2, we propose to use our AAV approach to examine Aβ-tau interactions in this diverse collection of APP transgenic models that exhibit different types of Aβ pathology. Additionally, in Aim 2, we will use pharmacologics and inducible APP models to examine the role of newly-made soluble Aβ vs long-lived insoluble Aβ in tau phosphorylation/aggregation process. Phospho-proteomic analysis will help us determine the relationship of different types of Aβ to the resulting tau phosphorylation profile. Collectively, this work will improve our understanding of the Aβ-driven phosphorylation cascade that appears to promote tau misfolding and aggregation into NFT.

摘要 阿尔茨海默病（AD）痴呆的临床症状发生在病理沉积的下游 Aβ肽在细胞外核心神经炎斑和聚集的tau蛋白在细胞内神经炎斑中的表达 神经纤维缠结（NFT）。由于在早发性家族性AD（fAD）中，Aβ沉积先于tau蛋白病， 接受Aβ可以触发tau蛋白错误折叠成NFT，引发一系列累积病理学， 逐渐导致痴呆在散发性AD中，Aβ的同时沉积似乎与tau蛋白相关。 错误折叠和NFT病理的严重程度。总的来说，这些发现表明Aβ沉积可以 加剧tau错误折叠和NFT形成，导致认知缺陷和痴呆。然而，底层 Aβ和tau协同作用导致NFT病理学和病理学 后遗症尚不清楚。我们的建议旨在提供实验性的见解，个人的贡献， 在AD小鼠模型中，tau（Aim 1）和Aβ（Aim 2）在驱动Aβ-tau协同作用中的作用。 有证据表明，Aβ与tau蛋白错误折叠协同作用的一个主要机制涉及蛋白质的降解。 tau蛋白的过度磷酸化。最近一项对AD患者的研究定量绘制了进展性 tau蛋白中磷酸化表位的出现鉴定了19个Ser/Thr残基， 在表现出并发Aβ病理的个体中磷酸化。目标1的主要目标是剖析 这些磷酸化事件在tau蛋白存在下发生的错误折叠和聚集中的作用 并发Aβ病变使用AAV技术，我们有能力产生和表达大量的 APP TgCRND 8小鼠中tau磷酸模拟变体的数量。使用这种小鼠模型，在目标1中，我们提出 一项广泛的研究，系统地剖析驱动tau蛋白错误折叠和NFT形成的磷酸化事件 在Aβ存在的情况下。 经过多年的研究，我们的实验室已经建立了表现出Aβ谱的小鼠模型， 病理学，包括主要发展弥漫性Aβ病理学的小鼠和主要发展核心- 神经炎病理学鉴于存在关于Aβ-tau蛋白基础的Aβ病理类型的问题， 协同作用，在目标2中，我们建议使用我们的AAV方法来检查Aβ-tau相互作用，在这个多样化的集合 显示不同类型Aβ病理的APP转基因模型。此外，在目标2中，我们将使用 药理学和诱导型APP模型，以检查新制备的可溶性Aβ与长寿命的不溶性A β的作用。 tau蛋白磷酸化/聚集过程中的Aβ。磷酸化蛋白质组学分析将帮助我们确定 不同类型的Aβ与产生的tau磷酸化谱的关系。 总的来说，这项工作将提高我们对Aβ驱动的磷酸化级联反应的理解， 似乎促进tau错误折叠和聚集成NFT。