title: NLRP3 inflammasome activation by mitochondrial reactive oxygen species plays a key role in long-term cognitive impairment induced by paraquat exposure.
abstract: Exposure to environmental toxins such as pesticides is implicated in increasing Alzheimer's disease risk. In this study, we investigated the long-term effects of paraquat exposure on cognition of Alzheimer's disease animal model APP/PS1 mice and wild-type (WT) mice. Our results showed that APP/PS1 mice had exacerbated cognition impairment and elevated Aβ levels at 5 months after paraquat exposure, and that WT mice had cognition impairment at 5 and 16 months after paraquat exposure. In addition, increased mitochondrial oxidative stress and augmented brain inflammation were observed in both paraquat-exposed APP/PS1 mice and WT mice. Interestingly, activation of NLRP3 inflammasome, which triggers inflammation in response to mitochondrial stress, was enhanced in paraquat-exposed mice. Moreover, transgenic mice overexpressing Prdx3, a key enzyme in detoxifying mitochondrial H2O2, had suppressed NLRP3 inflammasome activation, reduced brain inflammation, and attenuated cognition impairment after paraquat exposure. Together, our results indicate that NLRP3 inflammasome activation induced by mitochondrial reactive oxygen species plays a key role in mediating paraquat-induced long-term cognition decline by elevating brain inflammation.
authors.affiliation: Department of Cellular and Structural Biology; University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Liuji
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Cellular and Structural Biology; University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Ren
authors.initials: R
authors.lastname: Na
authors.affiliation: Department of Cellular and Structural Biology; University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Boldt
authors.affiliation: Department of Cellular and Structural Biology; University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA. Electronic address: ran@uthscsa.edu.
authors.forename: Qitao
authors.initials: Q
authors.lastname: Ran
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003072:Cognition Disorders / Q000139:chemically induced / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D010269:Paraquat / Q000633:toxicity*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D006540:Herbicides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins; C492716:Nlrp3 protein, mouse; C508853:PSEN1 protein, human; D053764:Presenilin-1; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D010269:Paraquat
keywords: Alzheimer's disease; Aβ; Inflammation; Mitochondria; NLRP3 inflammasome; Oxidative stress; Paraquat; Toxin exposure