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

作者：Di Tian, Yanmei Xing, Wenli Gao, Hongyan Zhang, Yifeng Song, Ya Tian, Zhongliang Dai · 发表于：Frontiers in Cell and Developmental Biology · 年份：2022 · DOI：10.3389/fcell.2021.801422 · 被引用次数：51 · 研究领域：Inflammasome and immune disorders、Intensive Care Unit Cognitive Disorders、Anesthesia and Neurotoxicity Research

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 β and interleukin-18, and increased β -amyloid (A β ) 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...