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.