PIAS1-mediated GSK3β SUMOylation exacerbates tauopathy and cognitive deficits in Alzheimer's disease models

Age-related neurodegenerative disorders, such as Alzheimer's disease (AD), are characterized by the accumulation of pathological Tau protein (tauopathy), which drives neurotoxicity and cognitive decline. Although SUMOylation significantly influences tauopathy, the underlying mechanisms remain largely elusive. Here, utilizing a bimolecular fluorescence complementation (BiFC) assay to monitor Tau-Tau aggregation and screen for SUMO E3 ligases, we identified PIAS1 as a critical driver of Tau pathology. Genetic analysis of the UK Biobank cohort revealed that single nucleotide polymorphisms in the PIAS1 gene (rs8036154 and rs112677781) are significantly associated with a reduced risk of AD. Consistent with this clinical relevance, PIAS1 expression is upregulated in postmortem AD brains, aging PS19 tauopathy mice, aged wild-type mice, aged lemurs, and neurons stimulated with amyloid-beta or lipopolysaccharide. Viral-mediated modulation of PIAS1 in vivo demonstrated that PIAS1 promotes Tau hyperphosphorylation and aggregation, thereby exacerbating synaptic dysfunction and cognitive deficits. Mechanistically, we found that PIAS1 directly interacts with and mediates the SUMOylation of glycogen synthase kinase 3 beta (GSK3β) at lysine residues 183 and 271. This specific SUMOylation reduces inhibitory phosphorylation at Ser9, consequently enhancing GSK3β-mediated Tau kinase activity. Importantly, we engineered a cell-permeable blocking peptide designed to disrupt the PIAS1-GSK3β interaction. Administration of this peptide effectively suppressed GSK3β activation and mitigated tauopathy and neurodegeneration in both in vitro and in vivo models. Together, our findings uncover a novel PIAS1-GSK3β signaling axis in tauopathy and provide a promising targeted therapeutic strategy for Alzheimer's disease.