Chronic hyperglycemia induces tau hyperphosphorylation by downregulating OGT-involved O-GlcNAcylation in vivo and in vitro

Objective: Diabetes mellitus (DM) can increase the risk of cognitive dysfunction, but its exact mechanisms remain unclear. The involvement of aberrant O-GlcNAcylation has been identified in hyperglycemia and DM, as well as the pathogenesis of Alzheimer's disease via competition with tau phosphorylation. This study was designed to investigate the role of O-GlcNAcylation in diabetes-associated cognitive dysfunction (DACD). Methods: Fifteen-week old male KK-Ay mice were used as DACD models, and advanced glycation end product (AGE)-treated HT22 cells were used as a model of high glucose toxicity. Morris water maze tests, histological staining, real-time quantitative PCR, and Western blot were also applied. Results: Mice with DACD exhibited evident obesity, hyperinsulinemia, hyperglycemia, and impaired learning and memory function. O-GleNAcylation levels decreased and tau phosphorylation levels at Ser396, Ser404, Thr212, and Thr231 increased in the hippocampus of mice with DACD, as well as in AGE-treated HT22 cells. Hypoglycemic therapy improved these anomalies and elevated O-GlcNAc transferase (OGT) levels in mice with DACD. OGT plasmid transfection in HT22 cells partially reversed AGE-induced decreases in O-GlcNAcylation levels and increased tau phosphorylation levels. Conclusions: Chronic hyperglycemia can induce tau hyperphosphorylation by downregulating OGT-involved OGlcNAcylation in vivo and in vitro, which mediates DACD.