Modifiers of Tau Seeds in Human Brain - Project Summary/Abstract: In diseases ranging from Alzheimer’s Disease to Frontotemporal Lobar Degeneration to Primary Age-Related Tauopathy, tau misfolds and progressively accumulates. Yet, when and how the earliest misfolding events occur still remain unknown. Cellular mechanisms exacerbating and alleviating tau seeding are critical therapeutic targets that are also not well defined. The overall goals of this work are, 1) to identify the distribution and amount of tau seeds in a range of human brains—diseased, clinically normal, young, and old— and, 2) to identify cellular factors, including biochemical modifications, co-pathologies, and inflammatory cellular responses that modulate tau seeding. Using ultrasensitive real-time quaking-induced conversion (RT- QuIC) seed amplification assays we have developed for 3R/4R tau, 4R tau, 3R tau, and a-synuclein, we aim to define the age of onset, amount, geography, and biochemical diversity of tau seeds in human brain and also to delineate how tau seeds are influenced by co-pathologies. We build on our significant preliminary and published evidence that tau seeds are common in the human brain and arise frequently in cases with low levels of neuropathology and even in absence of disease. First, this study focuses on disease relevant structures of human misfolded tau, and utilizes multifaceted approaches including seed detection methods (including for mixed misfolded protein co-pathologies), biochemical assays, immunomapping, and structural profiling to evaluate the impact of post-translational modifications. Second, proteomic, snRNAseq, and spatial transcriptomic methodologies will establish cellular states existing in the brain microenvironment prior to and across the range of disease stages. Third, we aim to elucidate the relatively unexplored functions of myeloid and glial cells in tau seed propagation and clearance, building on evidence that inflammatory reactive oxygen species can modify tau seeds and potently alter their subsequent seeding abilities. The biologic ramifications of finding ubiquitous tau seeds throughout neurodegenerative diseases, and even occurring in young adults, remain unknown. By identifying the cellular microenvironments and states that exist at the earliest detectable stages of tau seeding, we aim to identify critical and therapeutically tractable targets to block tau seeding at the most clinicopathologically impactful stages.
