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

作者：Tong Niu, Shaohua Wang, Haoqiang Zhang, Wenwen Zhu, K. J. Ray Liu, Xueling Zhou, Ruoyu Sun, Diejing Niu, Yang Yuan · 发表于：Experimental & Molecular Medicine · 年份：2025 · DOI：10.1038/s12276-025-01534-w · 被引用次数：5 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Alzheimer's disease research and treatments、Neurological Disease Mechanisms and Treatments

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...