Tau and GSK-3β are critical contributors to α-synuclein-mediated post-stroke brain damage

Abstract

Abstract Post-stroke secondary brain damage is significantly influenced by the induction and accumulation of α-Synuclein (α-Syn). α-Syn positive inclusions are often present in tauopathies and elevated Tau levels and phosphorylation promotes neurodegeneration. Glycogen synthase kinase 3β (GSK-3β) is a known promoter of Tau phosphorylation. We currently evaluated the interaction of α-Syn with GSK-3β and Tau in post-ischemic mouse brain. Transient focal ischemia led to increased cerebral protein-protein interaction of α-Syn with both GSK-3β and Tau, and elevated Tau phosphorylation. Treatment with a GSK-3β inhibitor prevented post-stroke Tau phosphorylation. Furthermore, α-Syn interaction was observed to be crucial for post-stroke GSK-3β-dependent Tau hyperphosphorylation as it was not seen in α-Syn knockout mice. Furthermore, Tau knockout mice show significantly smaller brain damage after transient focal ischemia. Overall, the present study indicates that GSK-3β catalyzes the α-Syn-dependent Tau phosphorylation and preventing this interaction is crucial to limit the post-stroke secondary brain damage.