Original Abstract

BACKGROUND: Diabetes-associated cognitive decline (DACD) is gradually gaining attention as a major complication of diabetes. However, to date, the specific molecular mechanisms underlying DACD have not been thoroughly characterized. METHODS: Db/db and streptozotocin (STZ) treated high-fat diet (HFD)-induced mice were established. Different behavioural assessments were performed, followed by evaluation of mitochondrial homeostasis, including mitochondrial morphology and function. Mitochondrial dynamics proteins, synaptic-related proteins and O-GlcNAc cycling enzymes were examined. Thereafter, OGT-interacting proteins were identified using co-immunoprecipitation mass spectrometry. Additionally, mouse hippocampal neuronal cells were treated with OGT siRNA and subsequent changes were measured. Mice were stereotaxically injected with adeno-associated viruses to overexpress OGT specifically in the hippocampus, and relevant in vivo experiments were performed. Finally, mice received semaglutide for 16 weeks and subsequent changes were assessed. RESULTS: Decreased OGT expression disrupted mitochondrial homeostasis and led to neuronal injury and cognitive impairment in diabetic mice. In addition, hippocampus-specific OGT overexpression improved DACD. Mechanistically, OGT deficiency resulted in a reduced mitochondrial membrane potential, promoting mitochondrial fission and impairing mitochondrial function by modulating DRP1 function. Furthermore, our results showed that semaglutide alleviated DACD through the OGT/DRP1 pathway. CONCLUSIONS: OGT deficiency-mediated mitochondrial homeostasis imbalance contributes to the occurrence of DACD, and semaglutide with an OGT protective effect may be a potential therapeutic approach for DACD.