<scp>SCD2</scp> Alleviates Diabetes‐Associated Cognitive Dysfunction by Improving Microglial Lipid Metabolism

The mechanisms underlying diabetes-associated cognitive dysfunction (DACD) are not fully understood, and microglial metabolic dysfunction is emerging as a key contributor. This study investigates whether stearoyl-CoA desaturase 2 (SCD2) alleviates cognitive impairment by modulating microglial lipid metabolism and function. Bioinformatics analysis of a single-cell RNA-seq dataset (GSE201644) identified SCD2 downregulation in diabetic (db/db) microglia. A T2D mouse model underwent hippocampal overexpression of SCD2 via AAV injection. In vitro, high glucose (HG)-treated BV2 microglia-like cells were subjected to SCD2 overexpression or oleic acid (OA) supplementation. Mitochondrial function (OCR, ATP, ETC complexes), lipid droplet accumulation (BODIPY, PLIN2), and inflammation (TNF-α, IL-6) were assessed. Cognitive behaviour (MWM, NOR) and neurophysiology (synaptic markers, neuronal survival) were evaluated. Diabetic microglia exhibited reduced SCD2 expression, impaired oxidative phosphorylation and lipid droplet accumulation (LDAM). SCD2 overexpression or OA rescued mitochondrial function, mitigated lipid droplet accumulation and attenuated inflammation. In vivo, hippocampal SCD2 overexpression attenuated neuroinflammation, preserved synaptic integrity and improved cognition in diabetic mice. SCD2 is essential for maintaining microglial lipid and mitochondrial homeostasis in diabetes. Restoring SCD2 function alleviates neuroinflammation and synaptic deficits, thereby rescuing cognitive impairment, highlighting its therapeutic potential for DACD.