Han Shuangxue, He Zhijun, Hu Xia, Li Xiaoqian, Zheng Kaixin, Huang Yingying, Xiao Peng, Xie Qingguo, Ni Jiazuan, Liu Qiong
Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, China.
College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China.
Antioxidants (Basel). 2023 Mar 15;12(3):722. doi: 10.3390/antiox12030722.
The reduction of the cerebral glucose metabolism is closely related to the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome in Alzheimer's disease (AD); however, its underlying mechanism remains unclear. In this paper, F-flurodeoxyglucose positron emission tomography was used to trace cerebral glucose metabolism in vivo, along with Western blotting and immunofluorescence assays to examine the expression and distribution of associated proteins. Glucose and insulin tolerance tests were carried out to detect insulin resistance, and the Morris water maze was used to test the spatial learning and memory ability of the mice. The results show increased NLRP3 inflammasome activation, elevated insulin resistance, and decreased glucose metabolism in 3×Tg-AD mice. Inhibiting NLRP3 inflammasome activation using CY-09, a specific inhibitor for NLRP3, may restore cerebral glucose metabolism by increasing the expression and distribution of glucose transporters and enzymes and attenuating insulin resistance in AD mice. Moreover, CY-09 helps to improve AD pathology and relieve cognitive impairment in these mice. Although CY-09 has no significant effect on ferroptosis, it can effectively reduce fatty acid synthesis and lipid peroxidation. These findings provide new evidence for NLRP3 inflammasome as a therapeutic target for AD, suggesting that CY-09 may be a potential drug for the treatment of this disease.
脑葡萄糖代谢的降低与阿尔茨海默病（AD）中NOD样受体蛋白3（NLRP3）炎性小体的激活密切相关；然而，其潜在机制仍不清楚。本文采用F-氟脱氧葡萄糖正电子发射断层扫描技术在体内追踪脑葡萄糖代谢，并结合蛋白质免疫印迹和免疫荧光分析检测相关蛋白的表达和分布。进行葡萄糖和胰岛素耐量试验以检测胰岛素抵抗，并使用莫里斯水迷宫测试小鼠的空间学习和记忆能力。结果显示，3×Tg-AD小鼠的NLRP3炎性小体激活增加、胰岛素抵抗升高且葡萄糖代谢降低。使用NLRP3特异性抑制剂CY-09抑制NLRP3炎性小体激活，可能通过增加葡萄糖转运蛋白和酶的表达及分布以及减轻AD小鼠的胰岛素抵抗来恢复脑葡萄糖代谢。此外，CY-09有助于改善这些小鼠的AD病理并缓解认知障碍。虽然CY-09对铁死亡无显著影响，但它可有效减少脂肪酸合成和脂质过氧化。这些发现为NLRP3炎性小体作为AD的治疗靶点提供了新证据，表明CY-09可能是治疗该疾病的潜在药物。
