Protection of MCC950 against Alzheimer's disease via inhibiting neuronal pyroptosis in SAMP8 mice
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RESEARCH ARTICLE
Protection of MCC950 against Alzheimer’s disease via inhibiting neuronal pyroptosis in SAMP8 mice Jie Li1,4 · Lili Zhuang3,4,5 · Xiaoqing Luo3,4,5 · Jianheng Liang3,4,5 · Erwei Sun2,3,4,5 · Yi He2,3,4,5 Received: 3 April 2020 / Accepted: 31 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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 Aβ1–42 by 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. Keywords Alzheimer’s disease · NLRP3 inflammasome · Neuronal pyroptosis · MCC950 · SAMP8 mice
Introduction
Communicated by Sreedharan Sajikumar. Jie Li and Lili Zhuang contributed equally to this work as co-first authors. * Erwei Sun [email protected] * Yi He [email protected] 1
Department of Neurology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
2
Department of Rheumatology and Immunology, Shunde Hospital, Southern Medical University, Foshan, China
3
Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
4
Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, Guangzhou, China
5
Institute of Clinical Immunology, Academy of Orthopedics of Guangdong Province, Guangzhou, China
Alzheimer’s disease (AD), a neurodegenerative disease, is characterized by progressive memory loss, cognitive decline, and abnormal mental behavior (Canter et al. 2016; Krishna et al. 2016). In previous research, analyses of the brains in AD patients showed that the presence of extracellular amyloid-β (Aβ) peptide, intracellular neurofibrillary tangle, and neuronal death were neuropathological hallmarks of the disease (Hardy and Selkoe 2002; Montine et al. 2012; Wang et al. 2015; Nisbet et a
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