NLRP3 炎性小体阻断作为早期阿尔茨海默病中中枢性胰岛素抵抗的潜在治疗方法。
NLRP3 Inflammasome Blocking as a Potential Treatment of Central Insulin Resistance in Early-Stage Alzheimer's Disease.
机构信息
Department of Biochemistry, Medical, Pharmaceutical & Toxicological Chemistry, Krasnoyarsk State Medical University Named after Prof. V.F. Voino-Yasenetsky, 660022 Krasnoyarsk, Russia.
Research Institute of Molecular Medicine and Pathobiochemistry, 660022 Krasnoyarsk, Russia.
出版信息
Int J Mol Sci. 2021 Oct 27;22(21):11588. doi: 10.3390/ijms222111588.
BACKGROUND
Alzheimer's disease (AD) is a devastating neurodegenerative disorder. In recent years, attention of researchers has increasingly been focused on studying the role of brain insulin resistance (BIR) in the AD pathogenesis. Neuroinflammation makes a significant contribution to the BIR due to the activation of NLRP3 inflammasome. This study was devoted to the understanding of the potential therapeutic roles of the NLRP3 inflammasome in neurodegeneration occurring concomitant with BIR and its contribution to the progression of emotional disorders.
METHODS
To test the impact of innate immune signaling on the changes induced by Aβ1-42 injection, we analyzed animals carrying a genetic deletion of the Nlrp3 gene. Thus, we studied the role of NLRP3 inflammasomes in health and neurodegeneration in maintaining brain insulin signaling using behavioral, electrophysiological approaches, immunohistochemistry, ELISA and real-time PCR.
RESULTS
We revealed that NLRP3 inflammasomes are required for insulin-dependent glucose transport in the brain and memory consolidation. Conclusions NLRP3 knockout protects mice against the development of BIR: Taken together, our data reveal the protective role of Nlrp3 deletion in the regulation of fear memory and the development of Aβ-induced insulin resistance, providing a novel target for the clinical treatment of this disorder.
背景
阿尔茨海默病（AD）是一种破坏性的神经退行性疾病。近年来，研究人员越来越关注研究大脑胰岛素抵抗（BIR）在 AD 发病机制中的作用。神经炎症由于 NLRP3 炎性小体的激活而对 BIR 有重大贡献。这项研究致力于了解 NLRP3 炎性小体在与 BIR 同时发生的神经退行性变中的潜在治疗作用及其对情绪障碍进展的贡献。
方法
为了测试先天免疫信号对 Aβ1-42 注射诱导的变化的影响，我们分析了携带 Nlrp3 基因缺失的动物。因此，我们使用行为、电生理方法、免疫组织化学、ELISA 和实时 PCR 研究了 NLRP3 炎性小体在维持大脑胰岛素信号中的作用在健康和神经退行性变中的作用。
结果
我们发现 NLRP3 炎性小体是大脑中胰岛素依赖的葡萄糖转运和记忆巩固所必需的。结论 NLRP3 敲除可保护小鼠免受 BIR 的发展：综上所述，我们的数据揭示了 Nlrp3 缺失在调节恐惧记忆和 Aβ 诱导的胰岛素抵抗中的保护作用，为该疾病的临床治疗提供了一个新的靶点。
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