Identification of AS1842856 as a novel small‐molecule GSK3α/β inhibitor against Tauopathy by accelerating GSK3α/β exocytosis

Glycogen synthase kinase‐3α/β (GSK3α/β) is a critical kinase for Tau hyperphosphorylation which contributes to neurodegeneration. Despite the termination of clinical trials for GSK3α/β inhibitors in Alzheimer's disease (AD) treatment, there is a pressing need for novel therapeutic strategies targeting GSK3α/β. Here, we identified the compound AS1842856 (AS), a specific forkhead box protein O1 (FOXO1) inhibitor, reduced intracellular GSK3α/β content in a FOXO1‐independent manner. Specifically, AS directly bound to GSK3α/β, promoting its translocation to the multivesicular bodies (MVBs) and accelerating exocytosis, ultimately decreasing intracellular GSK3α/β content. Expectedly, AS treatment effectively suppressed Tau hyperphosphorylation in cells exposed to okadaic acid or expressing the TauP301S mutant. Furthermore, AS was visualized to penetrate the blood–brain barrier (BBB) using an imaging mass microscope. Long‐term treatment of AS enhanced cognitive function in P301S transgenic mice by mitigating Tau hyperphosphorylation through downregulation of GSK3α/β expression in the brain. Altogether, AS represents a novel small‐molecule GSK3α/β inhibitor that facilitates GSK3α/β exocytosis, holding promise as a therapeutic agent for GSK3α/β hyperactivation‐associated disorders. AS1842856 (AS) inhibits Tauopathy via promoting glycogen synthase kinase‐3α/β (GSK3α/β) exocytosis. Upon entering the cell, AS binds to GSK3α/β and facilitates the translocation of GSK3α/β to early endosomes, which in turn promotes GSK3α/β accumulation in multivesicular bodies (MVBs) and subsequently reduces intracellular GSK3α/β contents via promoting GSK3α/β exocytosis. Reduced intracellular GSK3α/β inhibits Tau hyperphosphorylation and the formation of neurofibrillary tangles.