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<p>Diabetic encephalopathy (DE) is a prevalent complication of diabetes which can lead to cognitive dysfunction, without effective therapy currently. In diabetic patients, a reduction in adult hippocampal neurogenesis (AHN) is a heightened risk of cognitive impairment, which may be associated with neuroinflammation caused by microglia. In this study, we established a DE mouse model and conducted in vitro cultures of microglial cells and neural stem cells. Our study demonstrated that the high-glucose associated with DE impairs AHN and induces microglial NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) dependent pyroptosis. Further investigation showed that upregulation of microglial NLRP3 promotes the activation of Gasdermin D (GSDMD), the key pyroptosis effector, and the cleavage of pro-interleukin-1β (pro-IL-1β) by caspase-1, exacerbated pyroptosis and induced release of IL-1β, which might lead to impaired AHN and subsequent cognitive dysfunction. Conversely, downregulation of microglial NLRP3 inhibited caspase-1 activation and pyroptosis, reduced release of IL-1β, improved AHN, and rescued cognitive deficits in DE mouse model. Such findings suggest that targeting microglial NLRP3 inflammasome-mediated pyroptosis may be an important potential therapeutic target for treating DE.</p><p></p>

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Microglial NLRP3-dependent pyroptosis promotes cognitive dysfunction of diabetic encephalopathy by inhibiting adult hippocampal neurogenesis through the release of IL-1β

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月20日

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  • Meng-yu Hua,
  • Shan Huang,
  • Zi-yun Zhuang,
  • Xiao-lin Han,
  • Xiao-jing Liu,
  • Zhong-hao Liang,
  • Neng-jun Lou,
  • Feng-jie Zheng,
  • Li lv,
  • Xiang-hua Zhuang,
  • Shu-yan Yu,
  • Shi-hong Chen

摘要

Diabetic encephalopathy (DE) is a prevalent complication of diabetes which can lead to cognitive dysfunction, without effective therapy currently. In diabetic patients, a reduction in adult hippocampal neurogenesis (AHN) is a heightened risk of cognitive impairment, which may be associated with neuroinflammation caused by microglia. In this study, we established a DE mouse model and conducted in vitro cultures of microglial cells and neural stem cells. Our study demonstrated that the high-glucose associated with DE impairs AHN and induces microglial NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) dependent pyroptosis. Further investigation showed that upregulation of microglial NLRP3 promotes the activation of Gasdermin D (GSDMD), the key pyroptosis effector, and the cleavage of pro-interleukin-1β (pro-IL-1β) by caspase-1, exacerbated pyroptosis and induced release of IL-1β, which might lead to impaired AHN and subsequent cognitive dysfunction. Conversely, downregulation of microglial NLRP3 inhibited caspase-1 activation and pyroptosis, reduced release of IL-1β, improved AHN, and rescued cognitive deficits in DE mouse model. Such findings suggest that targeting microglial NLRP3 inflammasome-mediated pyroptosis may be an important potential therapeutic target for treating DE.