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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/摘要该项目的目标是捕获病理性tau蛋白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痴呆症病理生理学中的作用。最近的研究表明，微管的特征性时间和地形模式的相关性- 相关蛋白tau（MAPT）聚集与观察到的AD临床表型和进展有关。虽然神经元缠结（NFT）和其他形式的磷酸化tau聚集体被认为在神经元缠结中起作用。在疾病过程中起着关键作用，我们对它的组成和分子水平了解甚少。这些不溶性聚集体的环境，以及它们的形成，毒性和在特定大脑中的传播区域是规范的。更深入地了解AD和原发性tau蛋白病中的磷酸化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，神经元和神经胶质对于鉴定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是不可能的。夹杂物历来难以处理，因为这些聚集体是不溶于洗涤剂的，对经典的亲和纯化方法是难处理的。为了解决这个问题，我们建立了一个新的用于邻近标记、纯化和鉴定病理性磷酸化tau相关蛋白的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。我们假设病理性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。我们建议使用最新的尖端技术跨不同患者队列和疾病分析磷酸化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小鼠模型和人类类器官系统中的治疗靶点。我们的三个具体目标是：（一）比较通过磷酸化tau的邻近蛋白质组学跨常见tau蛋白病的tau病理学相关蛋白质组 AD和原发性tau蛋白病患者脑中的内含物，（ii）建立tau蛋白的时空模式脑区疾病阶段特异性病理相关蛋白质组和AD患者的脑弹性（iii）确定tau病理学相关蛋白在神经退行性疾病中的功能作用。通过在AD相关的tau蛋白病小鼠模型和人脑类器官中的靶点验证来进行过程。该项目的成功完成将导致新的分子成分的鉴定在AD和相关痴呆的发病过程中调节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。项目摘要/摘要第6页