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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos 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&apos 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

项目摘要

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.

抽象的阿尔茨海默病（AD）痴呆的临床症状发生在病理沉积的下游细胞外核心神经炎斑块中的 Aβ 肽和细胞内神经原纤维中聚集的 tau 蛋白由于早发性家族性 AD (fAD) 中 Aβ 沉积先于 tau 蛋白病变，因此它是大脑中的缠结 (NFT)。承认 Aβ 可以触发 tau 蛋白错误折叠成 NFT，引发一系列累积病理学，在散发性 AD 中，Aβ 的同时沉积似乎与 tau 相关。总的来说，这些发现表明 Aβ 沉积可以影响 NFT 的错误折叠和 NFT 病理的严重程度。加剧的 tau 错误折叠和 NFT 形成导致认知缺陷和痴呆。 Aβ 和 tau 协同作用导致 NFT 病理学和病理学的机制和特征我们的建议旨在为个人贡献提供实验见解。 tau（目标 1）和 Aβ（目标 2）在 AD 小鼠模型中驱动 Aβ-tau 协同作用。有证据表明，Aβ 与 tau 错误折叠协同作用的一个主要机制涉及最近对 AD 患者进行的一项研究定量描绘了 tau 蛋白的过度磷酸化。 tau 中磷酸化表位的出现确定了最常见的 19 个 Ser/Thr 残基目标 1 的主要目标是剖析 Aβ 病理的个体中的磷酸化。这些磷酸化事件在存在时发生的 tau 错误折叠和聚集中的贡献使用 AAV 技术，我们有能力生成和表达大量 Aβ 病理学。 APP TgCRND8 小鼠中 tau 磷酸化模拟变体的数量使用该小鼠模型，在目标 1 中我们提出。一项广泛的研究，系统地剖析驱动 tau 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，我们的实验室创建了具有 Aβ 谱的小鼠模型病理学，包括主要发展为弥漫性 Aβ 病理学的小鼠和主要发展为核心病理学的小鼠鉴于存在关于 Aβ-tau 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 方法来检查这个多样化集合中的 Aβ-tau 相互作用此外，在目标 2 中，我们将使用表现出不同类型 Aβ 病理学的 APP 转基因模型。药理学和诱导型 APP 模型，用于检验新制备的可溶性 Aβ 与长寿命不溶性 Aβ 的作用 tau 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 与所得 tau 磷酸化谱的关系。总的来说，这项工作将提高我们对 Aβ 驱动的磷酸化级联的理解，似乎会促进 tau 错误折叠并聚集成 NFT。