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.

doi:10.1101/2025.06.17.660179

bioRxiv · 10.1101/2025.06.17.660179

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.

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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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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.. 2025-06-20. Tau-seed interactome analysis reveals distinct functional signatures in Alzheimer's disease across model systems.. https://doi.org/10.1101/2025.06.17.660179

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