Fyn Kinase Controls Tau Aggregation  <i>in Vivo</i>

Abstract

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