title: NLRP3 Inflammasome Inhibitor Ameliorates Amyloid Pathology in a Mouse Model of Alzheimer's Disease.
abstract: 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 Aβ deposition and decreased levels of soluble and insoluble Aβ1-42in the brain of CRND8 mice which was accompanied by reduced β-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.
authors.affiliation: Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China.|Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Fanpeng
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Chojnacki
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Fulp
authors.affiliation: Department of Neurobiology, Northwestern University, Evanston, IL, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Klein
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA. szhang2@vcu.edu.
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA. xiongwei.zhu@case.edu.
authors.forename: Xiongwei
authors.identifier: http://orcid.org/0000-0003-2092-6508
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000682:Amyloid; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018696:Neuroprotective Agents; C492716:Nlrp3 protein, mouse
keywords: Alzheimer’s disease; Amyloid-beta; Inflammasome; NLRP3; Neuroinflammation