Fyn Kinase Controls Tau Aggregation In Vivo.

Alzheimer's disease (AD) is a proteinopathy exhibiting aggregation of β-amyloid (Aβ) as amyloid plaques and tau as neurofibrillary tangles (NFTs), whereas primary tauopathies display only a tau pathology. Aβ toxicity is mediated by Fyn kinase in a tau-dependent process; however, whether Fyn controls tau pathology in diseases that lack Aβ 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 synaptic 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 Aβ-induced toxicity and thereby represents a potentially valuable therapeutic target for not only AD but also tauopathies more generally.