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 Tau^P301S 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.