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PD/PI：Rossoll，Wilfried 项目摘要/摘要该项目的目的是捕获病理tau相关蛋白质组的分子复杂性阿尔茨海默氏病（AD）和相关的陶氏病患者的大脑，以获得彻底的机理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，微管的特征临时和地形模式相关与观察到的临床表型和AD进展的相关蛋白tau（MAPT）聚集体。尽管据信神经纤维缠结（NFT）和其他形式在疾病过程中的关键作用，我们对组成和分子的了解很差这些不溶性聚集体的环境，以及它们的形成，毒性和如何散布在特定的大脑中区域受到监管。对AD和原发性呼吸病中的磷酸-TAU相互作用组的更多了解，以及这些蛋白如何调节受影响的tau的寡聚，病理积累和播种神经元和神经胶质对于鉴定新的治疗靶标至关重要。作为当前技术的局限性，NFT和其他神经病理学的深入表征从历史上看对经典亲和力纯化方法的难治。为了解决这一限制，我们已经建立了一本小说接近标记，纯化和鉴定病理磷酸-TAU相关的方法来自固定人体组织的蛋白质，然后进行定量蛋白质组学分析。我们假设病理tau的分子环境和差异积累聚集体有助于AD和相关的tauopathies的病因。我们建议使用最新的尖端介绍不同患者队列和疾病的磷酸-TAU相关蛋白质组的技术阶段，在疾病发展中破译分子信号网络，并在功能上验证新型小鼠模型和人体器官系统中的治疗靶标。我们的三个具体目标是：（i）比较通过磷酸-TAU的接近蛋白质组学，跨tau病理相关的蛋白质组织与蛋白质组织相关的蛋白质组织 AD大脑和原发性tauopathy患者的夹杂物，（ii）建立tau的时空模式与大脑区域疾病阶段相关的病理相关蛋白质组和AD患者的大脑弹性队列和（iii）确定与Tau病理相关蛋白在神经退行性中的功能作用通过与广告相关的陶氏小鼠模型和人脑器官中的目标验证进行过程。该项目的成功完成将导致鉴定新的分子成分在AD和相关痴呆的发病机理期间调节扭曲性特异性疾病途径，这可能会提供新的治疗策略来有效治疗这些毁灭性疾病。项目摘要/摘要页面6