NCOA3 as a Key Regulator in Diabetic Cognitive Dysfunction

Diabetes-related cognitive dysfunction (DCD) represents a significant complication of diabetes mellitus, yet its underlying molecular mechanisms remain incompletely elucidated. In this study, we aimed to investigate the potential role of nuclear receptor coactivator 3 (NCOA3) in DCD pathogenesis using both conditional knockout (cKO) and lentivirus-mediated overexpression mouse models. Diabetes was induced through combined high-fat diet feeding and low-dose streptozotocin (STZ) administration. Comprehensive behavioral assessments, including novel object recognition test (NORT), Y-maze, and contextual fear conditioning (CFC), were performed alongside molecular analyses of NCOA3/AGO2 expression and downstream targets. Our results suggested a significant downregulation of NCOA3 expression in cortical and hippocampal tissues of diabetic mice. Genetic ablation of NCOA3 in forebrain excitatory neurons markedly appeared to exacerbate hippocampus-dependent cognitive deficits, while targeted hippocampal NCOA3 overexpression effectively ameliorated these impairments. At the mechanistic level, NCOA3 deficiency was associated with reduced protein levels of AGO2, along with downregulation of the synaptic markers synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95). In vitro studies using primary neuronal cultures indicated that high glucose treatment similarly reduced the expression of both NCOA3 and AGO2, while pharmacological inhibition or genetic knockdown of NCOA3 was found to significantly upregulate miR-138-5p levels. These findings collectively suggested a potential regulatory axis wherein NCOA3 is associated with synaptic plasticity via AGO2/miR-138-5p signaling, providing insights into DCD pathogenesis.