Sevoflurane Aggravates the Progress of Alzheimer's Disease Through NLRP3/Caspase-1/Gasdermin D Pathway

Tian, Di1,2,3; Xing, Yanmei1,2,3; Gao, Wenli1,2,3; Zhang, Hongyan2,3; Song, Yifeng1,2,3; Tian, Ya1,2,3; Dai, Zhongliang1,2,3

2022-01-19

10.3389/fcell.2021.801422

Frontiers in Cell and Developmental Biology   影响因子和分区

2296-634X

Background: Alzheimer's disease (AD) is the most common form of dementia worldwide. Previous studies have reported that sevoflurane, a frequently used anesthetic, can induce cognitive impairment in preclinical and clinical settings. However, the mechanism underlying the development of this neurotoxicity is currently unclear.Methods: Seven-month-old APP/PS1 mice were placed in an anesthesia induction box containing 3% sevoflurane in 100% O-2 for 6 h, while BV2 cells were cultured with 4% sevoflurane for 6 h. Pyroptosis and tau protein expression in excised hippocampus tissues and cells were measured using Western blotting and immunofluorescence assay. Caspase-1 and NLRP3 were knocked out in BV2 microglia using CRISPR/Cas9 technology to determine whether they mediate the effects induced by sevoflurane.Results: Sevoflurane directly activated caspase-1 to induce pyroptosis in the mouse model of AD via NLRP3 and AIM2 activation. In addition, sevoflurane mediated cleavage of gasdermin D (GSDMD) but not gasdermin E (GSDME), promoted the biosynthesis of downstream interleukin-1 beta and interleukin-18, and increased beta-amyloid (A beta) deposition and tau phosphorylation. The nontoxic caspase-1 small-molecule inhibitor VX-765 significantly inhibited this activation process in microglia, while NLRP3 deletion suppressed sevoflurane-induced caspase-1 cleavage and subsequently pyroptosis, as well as tau pathology. Furthermore, silencing caspase-1 alleviated the sevoflurane-induced release of IL-1 beta and IL-18 and inhibited tau-related enzymes in microglia.Conclusion: This study is the first to report that clinical doses of sevoflurane aggravate the progression of AD via the NLRP3/caspase-1/GSDMD axis. Collectively, our findings elucidate the crucial mechanisms of NLRP3/caspase-1 in pyroptosis and tau pathogenesis induced by sevoflurane and suggest that VX-765 could represent a novel therapeutic intervention for treating AD.

gasdermin D pyroptosis sevoflurane tau pathology VX-765

SCI

英语

通讯

Shenzhen Municipal Science and Technology Foundation[JCYJ20170307100314152] ; Shenzhen Healthcare Research Project["SZLY2018011","SZXJ2017029"] ; Guangdong Medical Research Fund["A2018008","A2019382"] ; Scientific Research Fund of Shenzhen People's Hospital[SYLY201706]

Cell Biology ; Developmental Biology

Cell Biology ; Developmental Biology

WOS:000749886500001

FRONTIERS MEDIA SA

Web of Science

1.Jinan Univ, Clin Med Coll 2, Shenzhen Peoples Hosp, Dept Anesthesiol, Shenzhen, Peoples R China
2.Southern Univ Sci & Technol, Affiliated Hosp 1, Dept Anesthesiol, Shenzhen, Peoples R China
3.Shenzhen Engn Res Ctr Anesthesiol, Shenzhen, Peoples R China

Tian, Di,Xing, Yanmei,Gao, Wenli,et al. Sevoflurane Aggravates the Progress of Alzheimer's Disease Through NLRP3/Caspase-1/Gasdermin D Pathway[J]. Frontiers in Cell and Developmental Biology,2022,9.

Tian, Di.,Xing, Yanmei.,Gao, Wenli.,Zhang, Hongyan.,Song, Yifeng.,...&Dai, Zhongliang.(2022).Sevoflurane Aggravates the Progress of Alzheimer's Disease Through NLRP3/Caspase-1/Gasdermin D Pathway.Frontiers in Cell and Developmental Biology,9.

Tian, Di,et al."Sevoflurane Aggravates the Progress of Alzheimer's Disease Through NLRP3/Caspase-1/Gasdermin D Pathway".Frontiers in Cell and Developmental Biology 9(2022).