Sevoflurane Aggravates the Progress of Alzheimer's Disease Through NLRP3/Caspase-1/Gasdermin D Pathway.
Front Cell Dev Biol
; 9: 801422, 2021.
Article
em En
| MEDLINE
| ID: mdl-35127716
ABSTRACT
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% O2 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-1ß and interleukin-18, and increased ß-amyloid (Aß) 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-1ß 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.
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Bases de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Front Cell Dev Biol
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
China