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

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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.