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<p>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.</p>

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Astrocytic SCAP deletion ameliorates diabetes-associated cognitive impairment by suppressing microglial neuroinflammation and lipid droplet accumulation via the LCN2–24p3R–mTOR axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月22日

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  • Kunyu Liu,
  • Haoqiang Zhang,
  • Wenwen Zhu,
  • Tong Niu,
  • Yonglian Hu,
  • Haiping Zhou,
  • Ruoyu Sun,
  • Junru Zhou,
  • Shaohua Wang,
  • Yang Yuan

摘要

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.