Cholesterol-driven pathological astrocytic responses in diabetes-associated cognitive impairment through astrocytic SCAP accumulation and NF-κB–C3 signaling modulation

The diabetic environment, characterized by hyperglycemia, advanced glycation end products and cerebral insulin resistance, triggers pathological astrocytic responses that contribute to cognitive decline in diabetes-associated cognitive impairment. Cholesterol accumulation in the brain, particularly in astrocytes, contributes to this pathological process. SCAP, a cholesterol sensor involved in lipid imbalances, regulates metabolic diseases, but its role in astrocytes remains unclear. C57BL/6J wild-type and astrocyte-specific SCAP knockout mice were fed a high-fat diet and treated with streptozotocin to induce type 2 diabetes mellitus (T2DM). Behavioral tests and hippocampal histology were performed at 28 weeks. We investigated the NF-κB-C3 signaling pathway to elucidate how SCAP induces pathological astrocytic responses under diabetic conditions. Cognitive function was assessed in patients with T2DM using the Montreal Cognitive Assessment (MoCA) and the mini-mental state examination (MMSE). We found elevated SCAP expression in the astrocytes of T2DM mice, correlated with cognitive dysfunction, impaired synaptic plasticity and altered astrocyte morphology. These effects were mitigated in astrocyte-specific SCAP knockout mice. SCAP elevation activates NF-κB by recruiting IκBα to the Golgi apparatus, promoting C3 transcription. Conversely, the inhibition of SCAP suppressed NF-κB activation. In patients with T2DM, serum C3 levels were higher in those with mild cognitive impairment, showing a U-shaped correlation with low-density lipoprotein-cholesterol (LDL-C) levels. These findings uncover a critical regulatory axis underlying astrocytic dysfunction, where SCAP mediates pathological astrocytic responses via the NF-κB-C3 pathway, with the Golgi acting as the platform for SCAP-driven activation. Here we highlight the interaction between cholesterol disorders and pathological astrocytic responses, presenting SCAP as a potential target for therapeutic intervention in diabetes-associated cognitive impairment. Research Hypothesis Illustration: SCAP and complement C3 play a role in cholesterol-driven astrocyte responses in diabetes-associated cognitive impairment. Astrocytic SCAP expression is abnormally increased in HFD/STZ-induced diabetic mice, impairing neuronal synaptic plasticity by activating the IκBα/NF-κB/C3 signalling pathway. Upregulated SCAP in astrocytes directly binds to IκBα, increasing its activation in the Golgi apparatus, which promotes NF-κB nuclear translocation and triggers complement C3 transcriptional activation and inflammatory immune responses, ultimately leading to neuronal and cognitive damage.