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

联系PD/PI：罗索尔，威尔弗里德 项目摘要/摘要 这个项目的目标是捕捉病理tau相关蛋白质组的分子复杂性。 对阿尔茨海默病(AD)及相关脑病患者的大脑进行研究，以获得彻底的发病机制 了解它们在这些痴呆的病理生理学中的作用。 最近的研究表明，微管的时间和地形特征模式之间存在相关性。 相关蛋白tau(MAPT)与观察到的AD的临床表型和进展有关。 尽管神经原纤维缠结(NFT)和其他形式的磷酸-tau聚集体被认为在 在疾病过程中起着举足轻重的作用，我们对它的组成和分子了解很少 这些不溶性聚集体的环境，以及它们的形成、毒性和如何在特定的大脑中扩散 地区是受监管的。对阿尔茨海默病和原发性变态反应性疾病中的磷酸-tau相互作用体有更多的了解， 以及这些蛋白质如何调节受影响的tau的寡聚化、病理性堆积和播种。 神经元和神经胶质细胞对于识别新的治疗靶点至关重要。 由于当前技术的局限性，NFTs和其他神经病理学的深入特征 夹杂物历来很难解决，因为这些聚集体是不溶于洗涤剂的，因此 经典的亲和纯化方法难以获得。为了解决这一局限，我们建立了一部小说 病理性磷酸化tau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。 我们假设，病理性tau的分子环境和差异蓄积 聚集体有助于AD和相关的肌萎缩侧索硬化症的病因。我们建议使用最新的尖端技术 在不同的患者队列和疾病中描述磷酸化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，并从功能上验证新的 小鼠模型和人类器官系统的治疗靶点。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越常见tau病的tau病理相关蛋白质组 阿尔茨海默病和原发性颈椎病患者脑内的包涵体，(II)建立tau的时空模式 阿尔茨海默病患者脑区疾病阶段的病理相关蛋白质组与脑弹性 以及(Iii)确定tau病理相关蛋白在神经退行性变中的功能作用 阿尔茨海默病相关的小鼠模型和人脑器官通过靶点验证的过程。 该项目的成功完成将导致新的分子成分的鉴定 在阿尔茨海默病和相关痴呆的发病过程中调节变态反应的特异性疾病通路 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

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