Protection of MCC950 against Alzheimer's disease via inhibiting neuronal pyroptosis in SAMP8 mice
Protection of MCC950 against Alzheimer's disease via inhibiting neuronal pyroptosis in SAMP8 mice
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MCC950 通过抑制 SAMP8 小鼠神经元焦亡来预防阿尔茨海默病
DOI：
10.1007/s00221-020-05916-6
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发表时间：
2020-09-06
影响因子：
2
通讯作者：
He, Yi
中科院分区：
文献类型：
--
作者：
Li, Jie;Zhuang, Lili;He, Yi
神经元功能障碍和丧失被认为是阿尔茨海默病（AD）认知功能障碍的原因之一，但神经元丧失在AD发病机制中的具体机制仍存在争议。本研究探讨了NLRP3炎症小体诱导的神经元焦亡在AD神经元丢失中的作用，并率先使用NLRP3抑制剂MCC950干预SAMP8小鼠的衰老加速治疗。在体外，用淀粉样蛋白-β1-42 （Aβ1-42）刺激经MCC950预处理的人原代神经元（HPNs），发现MCC950通过抑制神经元焦亡显著降低Aβ1-42的神经毒性。在体内，将SAMP8小鼠随机分为载药处理组和MCC950处理组，发现MCC950同样具有积极的治疗作用。MCC950的干预改善了SAMP8小鼠的空间记忆能力和脑组织形态学，减少了脑内淀粉样蛋白-β的沉积。免疫荧光染色发现MCC950对SAMP8小鼠神经元焦亡反应因子NLRP3、caspase-1和GSDMD的过表达有抑制作用。在本研究中，我们发现NLRP3/caspase-1/GSDMD轴诱导的神经元焦亡是AD神经元丢失的重要因素，并揭示MCC950可能是一种潜在的AD治疗剂。
Neuronal dysfunction and loss are thought to be one of the causes of cognitive impairment in Alzheimer's disease (AD), but the specific mechanism of neuronal loss in the pathogenesis of AD remains controversial. This study explored the role of NLRP3 inflammasome-induced neuronal pyroptosis in neuronal loss of AD, and pioneered the use of NLRP3 inhibitor MCC950 to intervene in the treatment of senescence-accelerated mouse prone 8 (SAMP8) mice. In vitro, human primary neurons (HPNs) pretreated with MCC950 were stimulated with amyloid-β1–42(Aβ1–42), and it was found that MCC950 significantly reduced the neurotoxicity of Aβ1–42by inhibiting neuronal pyroptosis. In vivo, SAMP8 mice were randomly divided into vehicle-treated group and MCC950-treated group, and it was found that MCC950 also played a positive role in treatment. The intervention of MCC950 improved the spatial memory ability and brain histological morphology of SAMP8 mice, and reduced the deposition of amyloid-β in the brain. Furthermore, MCC950 was found to inhibit the overexpressions of NLRP3, caspase-1, and GSDMD, which were the response factors of pyroptosis in SAMP8 mouse neurons, by immunofluorescence staining. In this study, we found that neuronal pyroptosis induced by the NLRP3/caspase-1/GSDMD axis was an important factor in neuronal loss of AD, and revealed that MCC950 might be a potential AD therapeutic agent.