Reticulocalbin-2 in the Hippocampus Improves Cognitive Function of Diabetic Mice.

PURPOSE: To investigate the underlying mechanism linking diabetes to an increased risk of Alzheimer's disease (AD), specifically by examining the role of reticulocalbin-2 (RCN2) in the hippocampus. METHODS: Diabetes-associated cognitive impairment was examined using db/db mice on a C57BL/6J background. Genetic and virus-mediated approaches were employed to achieve hippocampal knockdown, conditional deletion, or overexpression of RCN2. Cognitive function and synaptic integrity were assessed using behavioral, molecular, and histological analyses. In addition, the GSK3β-Tau signaling pathway was analyzed to explore the molecular mechanisms underlying RCN2-mediated synaptic regulation. FINDING: This study reveals that decreased expression of RCN2 in the hippocampus is associated with cognitive impairment. Knockdown of hippocampal RCN2 directly led to cognitive decline and synaptic damage. Mechanistically, RCN2 functions by inhibiting the GSK3β-Tau pathway, thereby delaying synaptic loss. Importantly, overexpression of RCN2 in the hippocampus was found to partially rescue cognitive decline, demonstrating its therapeutic potential for Alzheimer's disease in a diabetic mouse model. CONCLUSION: The findings suggest that RCN2 is a key neuroprotective protein, and targeting RCN2 could represent a promising therapeutic strategy for neurodegenerative diseases like Alzheimer's, particularly in the context of diabetes.