Fyn Kinase Controls Tau Aggregation In Vivo

Alzheimer's disease (AD) is a proteinopathy exhibiting aggregation of beta-amyloid (A beta) as amyloid plaques and tau as neurofibrillary tangles (NFTs), whereas primary tauopathies display only a tau pathology. A beta toxicity is mediated by Fyn kinase in a tau-dependent process; however, whether Fyn controls tau pathology in diseases that lack A beta pathology remains unexplored. To address this, we generate the Tg/Fyn(-/-) mouse, which couples mutant tau overexpression with Fyn knockout. Surprisingly, Tg/Fyn(-/-) mice exhibit a near-complete ablation of NFTs, alongside reduced tau hyperphosphorylation, altered tau solubility, and diminished synap- tic tau accumulation, Furthermore, Tg/Fyn(-/-) brain lysates elicit less tau seeding in tau biosensor cells, Lastly, the fibrillization of tau is boosted by its pseudophosphorylation at the Fyn epitope Y18. Together, this identifies Fyn as a key regulator of tau pathology independently of A beta-induced toxicity and thereby represents a potentially valuable therapeutic target for not only AD but also tauopathies more generally.