Abstract
Abstract
Diabetes-associated cognitive impairment (DACI) is a prevalent and debilitating complication of type 2 diabetes, yet the mechanisms linking metabolic dysregulation to neuroinflammation and cognitive decline remain incompletely understood. In this study, we identify astrocytic SCAP (SREBP cleavage-activating protein) as a crucial regulator of glial metabolic–inflammatory crosstalk in DACI. Using a high-fat diet-induced mouse model of diabetes, we demonstrate that astrocytic SCAP expression is significantly upregulated, whereas astrocyte-specific SCAP deletion alleviates cognitive deficits, reduces microglial activation, and attenuates lipid droplet accumulation in the hippocampus. Transcriptomic analysis of SCAP-deficient mice identified lipocalin-2 (LCN2) as a prominent downstream candidate associated with inflammatory regulation. Mechanistically, astrocytic SCAP promotes NF-κB–dependent LCN2 expression, leading to LCN2-dependent paracrine activation of microglial 24p3R–mTOR signaling and consequent microglial inflammatory activation and lipid droplet accumulation. Consistently, pharmacological inhibition of mTOR or antibody-mediated blockade of LCN2 in vivo significantly ameliorated hippocampal neuroinflammation, neuronal injury, and cognitive decline in diabetic mice. These findings reveal a novel SCAP–LCN2–24p3R–mTOR signaling axis that links astrocytic lipid sensing to microglial inflammatory and metabolic dysfunction, providing a mechanistic framework for metabolic-inflammatory coupling in DACI and highlighting this pathway as a potential therapeutic target for DACI.