Fyn-dependent Tau microcluster formation seeds and boosts extensive Tau pathology.

Tau seeding and propagation are defining features of all tauopathies, including Alzheimer's disease, but the underlying molecular drivers remain incompletely understood. Here, we reveal that Fyn expression boosts massive Tau pathology in the mouse brain and enhances Tau seeding induced by pathological Tau seeds in biosensor cells. However, even in the absence of seeds, Fyn itself, via its palmitoylation, triggers the de novo formation of small, plasma membrane-anchored Tau microclusters, which initiate pronounced and diverse intra- and transcellular Tau seeding in vitro and in vivo. Mechanistically, membrane-associated Fyn phosphorylates Tau at its Tyr310 epitope and then recruits and activates GSK3β locally, which further phosphorylates Tau at Ser/Thr sites in the microclusters, eliciting their full seeding capacity. Our data suggest that Fyn not only serves as a master switch that initiates Tau pathogenesis on its own, but also augments a pre-existing Tau pathology, leading to a vicious cycle of Tau aggregation.