期刊
MOLECULAR NEUROBIOLOGY
卷 55, 期 3, 页码 1977-1987出版社
HUMANA PRESS INC
DOI: 10.1007/s12035-017-0467-9
关键词
Alzheimer's disease; Amyloid-beta; Inflammasome; Neuroinflammation; NLRP3
资金
- National Institute on Aging of the National Institutes of Health [R01NS083385, RFAG049479, R01AG041161]
- Alzheimer's Association [AARG-16-443584]
- Dr. Robert M. Kohrman Memorial Fund
- Alzheimer's Drug Discovery Foundation [20150601]
- National Natural Sciences Foundation of China [81100594]
The activation of the NLRP3 inflammasome signaling pathway plays an important role in the neuroinflammation in Alzheimer's disease (AD). In this study, we investigated the effects of JC-124, a rationally designed NLRP3 inflammasome inhibitor, on AD-related deficits in CRND8 APP transgenic mice (TgCRND8). We first demonstrated increased formation and activation of NLRP3 inflammasome in TgCRND8 mice compared to non-transgenic littermate controls, which was inhibited by the treatment with JC-124. Importantly, JC-124 treatment led to decreased levels of A beta deposition and decreased levels of soluble and insoluble A beta(1-42) in the brain of CRND8 mice which was accompanied by reduced beta-cleavage of APP, reduced activation of microglia but enhanced astrocytosis. Oxidative stress was decreased and synaptophysin was increased in the CRND8 mice after JC-124 treatment, demonstrating a neuroprotective effect. Overall, these data demonstrated beneficial effects of JC-124 as a specific NLRP3 inflammasome inhibitor in AD mouse model and supported the further development of NLRP3 inflammasome inhibitors as a viable option for AD therapeutics.
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