Tau and GSK-3β are Critical Contributors to α-Synuclein-Mediated Post-Stroke Brain Damage.

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-ischemic tau phosphorylation. Furthermore, α-Syn interaction was observed to be crucial for post-ischemic GSK-3β-dependent tau hyperphosphorylation as it was not seen in α-Syn knockout mice. Moreover, 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 post-ischemic secondary brain damage.