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

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 细胞外神经炎核心斑块中Aβ多肽和细胞内神经原纤维中聚集的tau蛋白 大脑中的缠结(NFT)。由于在早发性家族性阿尔茨海默病(FAD)中，Aβ的沉积先于转位病，因此 公认β可以触发tau错误折叠成NFT，启动一系列累积病理， 逐渐导致痴呆症。在散发性AD中，Aβ的一致沉积似乎与tau相关 错误折叠和NFT病理的严重性。总而言之，这些发现表明，β沉积可以 加剧tau错误折叠和NFT形成，导致认知缺陷和痴呆症。然而，潜在的 A-β和tau协同作用导致神经纤维母细胞瘤病理改变的机制和特点 后遗症仍不清楚。我们的提案旨在提供对个人贡献的试验性见解 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。 证据表明，Aβ与tau错误折叠协同作用的一个主要机制涉及 Tau蛋白的过度磷酸化。最近对AD患者进行的一项研究定量绘制了进展性的 在tau中出现的磷酸化表位确定了最常见的19个Ser/Thr残基 同时表现为Aβ病理的个体中的磷酸化。目标1的主要目标是剖析 这些磷酸化事件在存在时tau错误折叠和聚集中的贡献 并发的Aβ病理。使用AAV技术，我们有能力生成和表达大量 APP TgCRND8小鼠中tau磷酸化模拟变异体的数量。利用这个小鼠模型，我们在目标1中提出了 一项系统剖析导致tau错误折叠和NFT形成的磷酸化事件的广泛研究 在一个β面前。 经过多年的研究，我们的实验室已经创造出了表现出β谱系的小鼠模型 病理，包括主要发展为弥漫性Aβ病理的小鼠和主要发展为核心- 神经症病理学。鉴于存在关于Aβ病理类型的问题，Aβ-tau是其基础 协同，在目标2中，我们建议使用我们的AAV方法来研究这个不同集合中的β-tau相互作用 表现出不同类型的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模型检验新制成的可溶性A-β与长寿不溶性的作用 Aβ参与tau蛋白的磷酸化/聚集过程。磷酸蛋白质组学分析将帮助我们确定 不同类型的Aβ与由此产生的tau磷酸化图谱的关系。 总体而言，这项工作将提高我们对β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。

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.