Tau-seed interactome analysis reveals distinct functional signatures in Alzheimer's disease across model systems.
Martinez, P.; Patel, H.; You, Y.; Lopes, D.; Amaro, A.; Jury-Garfe, N.; Min, Y.; Redding-Ochoa, J.; Dutta, S.; Rochet, C.; Ertekin-Taner, N.; Troncoso, J.; Lasagna-Reeves, C. A.
Show abstract
Tau aggregates propagate through the brain in a prion-like manner in Alzheimers disease (AD) and other tauopathies, but the molecular identity and functional partners of the seeding-competent Tau species remain poorly defined. Here, we present an unbiased proteomic profiling of a high-molecular-weight (HMW) Tau-seed isolated from AD patient brains. We contrast this interactome with that of a biochemically similar, seeding-incompetent HMW-Tau species from age-matched healthy controls. Despite comprising less than 5% of total Tau in the brain, Tau-seed associates with a distinct set of proteins enriched in synaptic, mitochondrial, and vesicle-trafficking functions. Cross-species functional screening in Drosophila and mouse models identifies interactors that modulate Tau toxicity and seeding. Spatially resolved analysis of postmortem AD brains reveals heterogenous co-deposition of these proteins with Tau aggregates, suggesting functionally distinct Tau-seed complexes. Together, this dataset provides a framework for understanding selective Tau-seed toxicity and identifies candidate regulators of Tau propagation with therapeutic potential.
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