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

• 批准号: 10525133
• 负责人: Wilfried Rossoll
• 金额: $ 218.34万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10525133
• 关键词: Address; Affect; Affinity Chromatography; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Animal Model; Antibodies; Atrophic; Autopsy; Brain; Brain region; Cause of Death; Cell Culture Techniques; Cell model; Characteristics; Clinic; Complex; Data; Dementia; Detergents; Development; Disease; Disease Progression; Environment; Etiology; Formalin; Future; Goals; Human; Immunohistochemistry; In Vitro; Investigation; Label; Lesion; MAPT gene; Mass Spectrum Analysis; Methods; Modeling; Molecular; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neuroglia; Neurons; Organoids; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Pick body; Play; Post-Translational Protein Processing; Process; Property; Protein Isoforms; Proteins; Proteome; Proteomics; Quality Control; Refractory; Resolution; Role; Sampling; Signal Transduction; Tauopathies; Technology; Testing; Toxic effect; Transgenic Mice; United States; Variant; base; brain tissue; cell type; clinical phenotype; cohort; digital; effective therapy; human tissue; in vivo; interest; mouse model; neuropathology; new therapeutic target; novel; novel therapeutic intervention; phosphoproteomics; protein aggregation; proteostasis; resilience; spatiotemporal; tau Proteins; tau aggregation; tau conformation; tau phosphorylation; tau-1

PROJECT SUMMARY/ABSTRACT The goal of this project is to capture the molecular complexity of pathological tau-associated proteins in the brain of Alzheimer’s disease (AD) and related tauopathy patients via proximity-proteomics and gain a thorough mechanistic understanding of their role in the progression of tau pathology and associated neurodegeneration. Previous studies suggest a correlation of characteristic temporal and topological patterns of microtubule- associated protein tau (MAPT) aggregates with the observed clinical phenotype and the progression of the disease. 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 the brain regions is regulated. A better 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 of pathological tau aggregates contributes to the AD disease process and propose to use the latest cutting-edge technologies to determine and compare 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 human AD cases, mouse models, and human organoid models. 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, brain regions, and brain resilience in AD patient cohorts, and (iii) to determine the functional role of tau pathology-associated proteins in neurodegenerative processes in human AD cases, mouse models, and human brain organoids. Successful completion of this project will identify novel molecular components and cellular pathways regulating the pathogenesis of AD and primary tauopathies, which may provide new therapeutic strategies for effective treatment of these devastating disorders.

项目摘要/摘要 该项目的目的是捕获病理性tau相关蛋白的分子复杂性 阿尔茨海默氏病（AD）和相关的tauopathy患者的大脑通过接近性蛋白酶学并获得彻底的 对它们在TAU病理和相关神经变性进展中的作用的机理理解。 先前的研究表明，微管的特征临时和拓扑模式相关 与观察到的临床表型和相关蛋白tau（MAPT）聚集体 疾病。尽管神经原纤维缠结（NFT）和其他形式的磷酸tau骨料被认为是 在疾病过程中起关键作用，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，毒性和如何遍布大脑 区域受到监管。更好地理解AD和原发性呼吸疾病中的磷酸-TAU相互作用组， 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骨料的分子环境有助于AD 疾病过程和建议使用最新的尖端技术来确定和比较 在不同的患者队列和疾病阶段，磷酸-TAU相关的蛋白质组，以破译分子 疾病发展中的信号网络，并在功能上验证人类广告中的新型治疗靶标 案例，小鼠模型和人体器官模型。我们的三个具体目的是：（i）比较tau病理学 - 通过磷酸-TAU夹杂物的接近蛋白质组学在常见的tauopathies中相关蛋白质组织 AD和原发性tauopathy患者的大脑，（ii）建立tau病理的时空模式 - 相关的蛋白质组针对疾病阶段，大脑区域和脑部弹性特异 （iii）确定与Tau病理相关蛋白在神经退行性过程中的功能作用 在人类AD病例中，小鼠模型和人脑器官。 该项目的成功完成将确定新的分子组件和细胞途径 调节AD的发病机理和原发性呼吸病的发病机理，这可能为新的治疗策略提供 有效治疗这些毁灭性疾病。