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

www.nature.com/emm ARTICLE OPEN Cholesterol-driven pathological astrocytic responses in diabetes-associated cognitive impairment through astrocytic SCAP accumulation and NF-κB–C3 signaling modulation 1234567890();,: © The Author(s) 2025 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 NFκB 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. Experimental & Molecular Medicine (2025) 57:2083–2105; https://doi.org/10.1038/s12276-025-01534-w A full list of authors and their affiliations appears at the end of the paper. Received: 2 December 2024 Revised: 13 May 2025 Accepted: 28 May 2025 Published online: 29 September 2025 T. Niu et al 2084 Graphical Abstract Research Hypothesis Illustration: SCAP and complement C3 play a role in cholesterol-driven astrocyte responses in diabetesassociated 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. INTRODUCTION The global prevalence of diabetes mellitus (DM) is projected to exceed 640 million by the year 20401,2. One of the major neurodegenerative comorbidities of DM is diabetes-associated cognitive impairment (DACI), which affects ~13.5% of patients with diabetes, with prevalence rates exceeding 24.2% in individuals over the age of 75 years3,4. DACI is characterized by cognitive decline, which ranges from mild cognitive impairment (MCI) to dementia, the latter representing the most severe form and the second leading cause of death among patients with diabetes5,6. These cognitive impairments impede glycemic control, thereby increasing the risk of life-threatening complications such as hypoglycemia, hyperglycemic hyperosmotic coma and ketoacidosis. Therefore, understanding the complex pathophysiology underlying cognitive decline in individuals with diabetes represents an urgent research priority. Patients with diabetes frequently exhibit alterations in cholesterol metabolism7,8. Previous studies have shown that insulin resistance and hyperglycemia can disrupt cholesterol metabolism in the brain9. Furthermore, chronic hypercholesterolemia, which begins in midlife and persists into older age, is associated with an increased risk of Alzheimer’s disease (AD)10–12, particularly as these hypercholesterolemia often overlap with obesity, metabolic syndrome and diabetes. Our previous studies demonstrated that patients with type 2 DM (T2DM) are more likely to exhibit abnormal lipid metabolism, especially cholesterol production, and metabolic disorders in the brain13–15. Collectively, these findings underscore an important relationship among diabetes, cholesterol metabolism and cognitive decline. Sterol regulatory element binding protein (SREBP) cleavageactivating protein (SCAP) is a cholesterol sensor that regulates intracellular cholesterol homeostasis through signal transduction16–18. The dysregulation of SCAP impairs cholesterol homeostasis and lipid metabolism, contributing to metabolic diseases such as obesity, T2DM and cardiovascular disorders. Previous studies have demonstrated that SCAP is involved in the molecular mechanisms linking cholesterol metabolism directly to NLRP3 inflammasome activation19 and nuclear factor kappa B (NFκB) signaling20. Inflammatory factors can further increase SCAP expression, promoting the translocation of the SCAP/SREBP2 complex from the endoplasmic reticulum (ER) to the Golgi apparatus, which disrupts cholesterol homeostasis and contributes to conditions such as atherosclerosis21,22 and nonalcoholic fatty liver disease23. SCAP dysfunction also triggers an inflammatory activation in macrophages24,25. These findings suggest that SCAP is a key intermediary linking cholesterol metabolism to inflammation, making it an attractive therapeutic target for metabolic diseases. Moreover, abnormal cholesterol metabolism is associated with the initiation of inflammation, amyloid-beta production and accumulation, tau protein phosphorylation and synaptic damage26,27. However, the impact of cholesterol metabolism on learning and memory in diabetic mice remains underexplored, and the role of SCAP in the pathophysiology of DACI is yet to be fully elucidated. Astrocytes, essential for maintaining central nervous system (CNS) homeostasis and defense, play a vital role in cholesterol synthesis and metabolism within the brain28,29. Emerging evidence suggests that astrocytes are highly responsive to lifestyle changes and that their adaptability and plasticity may be crucial for favorable patient outcomes. Astrocyte morphology is particularly sensitive to environmental conditions30,31. For example, chronic overnutrition or sustained astrocytic IKKβ/NF-κB activation in astrocytes has been shown to induce astroc (...truncated)