Capturing the molecular complexity of tau pathology-associated proteomes involved in the etiology of Alzheimer's disease and related dementias

捕获与阿尔茨海默病和相关痴呆病因学相关的 tau 病理相关蛋白质组的分子复杂性

基本信息

批准号：
10763607
负责人：
Wilfried Rossoll
金额：
$ 30.42万
依托单位：
MAYO CLINIC JACKSONVILLE
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：
2022-09-15 至 2025-08-31
项目状态：
未结题

项目摘要

Contact PD/PI: Rossoll, Wilfried PROJECT SUMMARY/ABSTRACT The goal of this project is to capture the molecular complexity of pathological tau-associated proteomes in the brain of Alzheimer’s disease (AD) and related tauopathy patients, in order to gain a thorough mechanistic understanding of their role in the pathophysiology of these dementias. Recent studies suggest a correlation of characteristic temporal and topographic patterns of microtubule- associated protein tau (MAPT) aggregates with the observed clinical phenotype and progression of AD. Although neurofibrillary tangles (NFTs) and other forms of phospho-tau aggregates are believed to play a pivotal role in the disease process, we have a poor understanding of the composition and molecular environment of these insoluble aggregates, and how their formation, toxicity, and spread across specific brain regions is regulated. Greater understanding of the phospho-tau interactome in AD and primary tauopathies, and how these proteins regulate the oligomerization, pathological accumulation, and seeding of tau in affected neurons and glia is of critical importance for the identification of novel therapeutic targets. As a limitation of current technologies, the in-depth characterization of NFTs and other neuropathologic inclusions has historically been difficult to address, since these aggregates are detergent-insoluble, and thus refractory to classical affinity purification methods. To address this limitation, we have established a novel method for the proximity-labeling, purification and identification of pathological phospho-tau associated proteins from fixed human tissue followed by quantitative proteomics analysis. We hypothesize that the molecular environment and differential accumulation of pathological tau aggregates contributes to etiology of AD and related tauopathies. We propose to use the latest cutting-edge technologies to profile the phospho-tau associated proteome across different patient cohorts and disease stages, to decipher molecular signaling networks in disease development, and to functionally validate novel therapeutic targets in mouse models and human organoid systems. Our three specific aims are: (i) to compare tau pathology-associated proteomes across common tauopathies via proximity proteomics of phospho-tau inclusions in the brain of AD and primary tauopathy patients, (ii) to establish spatiotemporal patterns of tau pathology-associated proteomes specific for disease stages in brain regions, and brain resilience in AD patient cohorts, and (iii) to determine the functional role of tau pathology-associated proteins in neurodegenerative processes through target validation in AD-related tauopathy mouse models and human brain organoids. Successful completion of this project will result in the identification of novel molecular components regulating tauopathy-specific disease pathways during the pathogenesis of AD and related dementias, which may provide new therapeutic strategies for effective treatment of these devastating disorders. Project Summary/Abstract Page 6

联系人 PD/PI：Rossoll、Wilfried 项目概要/摘要该项目的目标是捕获病理性 tau 相关蛋白质组的分子复杂性阿尔茨海默病 (AD) 和相关 tau 蛋白病患者的大脑，以获得彻底的机制了解它们在这些痴呆症的病理生理学中的作用。最近的研究表明微管的特征时间和地形模式之间存在相关性相关蛋白 tau (MAPT) 与观察到的 AD 临床表型和进展发生聚集。尽管神经原纤维缠结 (NFT) 和其他形式的磷酸 tau 聚集体被认为发挥着在疾病过程中发挥着关键作用，但我们对其成分和分子了解甚少这些不溶性聚集物的环境，以及它们的形成、毒性和在特定大脑中的传播更好地了解 AD 和原发性 tau 病中的磷酸 tau 相互作用组，以及这些蛋白质如何调节受影响的 tau 蛋白的寡聚化、病理性积累和播种神经元和神经胶质细胞对于识别新的治疗靶点至关重要。作为当前技术的限制，NFT 和其他神经病理学的深入表征夹杂物历来难以解决，因为这些聚集体不溶于洗涤剂，因此为了解决这一局限性，我们建立了一种新颖的亲和纯化方法。病理性磷酸-tau相关蛋白的邻近标记、纯化和鉴定方法从固定的人体组织中提取蛋白质，然后进行定量蛋白质组学分析。我们探讨了病理性tau蛋白的分子环境和差异积累聚集体有助于 AD 和相关 tau蛋白病的病因学研究。分析不同患者群体和疾病中磷酸 tau 相关蛋白质组的技术阶段，破译疾病发展中的分子信号网络，并在功能上验证新的我们的三个具体目标是：（i）比较小鼠模型和人类类器官系统的治疗目标。通过磷酸化 tau 的邻近蛋白质组学研究常见 tau 病的 tau 病理相关蛋白质组 AD 和原发性 tau 病患者大脑中的包涵体，(ii) 建立 tau 蛋白的时空模式 AD 患者大脑区域疾病阶段特异的病理相关蛋白质组和大脑恢复能力 (iii) 确定 tau 病理相关蛋白在神经退行性疾病中的功能作用通过 AD 相关 tau 蛋白病小鼠模型和人脑类器官中的目标验证进行过程。该项目的成功完成将导致新型分子成分的鉴定在 AD 和相关痴呆的发病机制中调节 tau 蛋白病特异性疾病途径，可能为有效治疗这些破坏性疾病提供新的治疗策略。项目总结/摘要第 6 页