The anesthetic sevoflurane induces tau trafficking from neurons to microglia

Dong, Yuanlin; Liang, Feng; Huang, Liyi; Fang, Fang; Yang, Guang; Tanzi, Rudolph E.; Zhang, Yiying; Quan, Qimin; Xie, Zhongcong

doi:10.1038/s42003-021-02047-8

Cited by 44 publications

(39 citation statements)

References 79 publications

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“…The formation of A β plaques followed by sustained neuroinflammation was also found to be a crucial cause of cognitive disorder in an App-KI mouse model of AD ( Maloney and Lahiri, 2011 ). The innate immune response is a complex physiological process that occurs around microglia, which plays a key role in the development of some of the main pathological features of AD ( Li et al, 2017 ; Dong et al, 2021 ). Under normal conditions, intracerebral microglia maintain the balance between tau and Aβ deposition and clearance ( Tang et al, 2011 ; Xue et al, 2020 ); and several studies have implicated microglial dysfunction in the pathogenesis of AD ( He et al, 2015 ; Sung et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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

Tian

Xing

Gao

et al. 2022

Front. Cell Dev. Biol.

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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-1β and interleukin-18, and increased β-amyloid (Aβ) 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-1β 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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Section: Introductionmentioning

confidence: 99%

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

Tian

Xing

Gao

et al. 2022

Front. Cell Dev. Biol.

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“…For example, young mice repeatedly exposed to sevoflurane, a widely used inhalational anesthetic, exhibit abnormal social and impulsive behavior, deficits in motor learning, and impairments in fear and spatial memory (Le Freche et al, 2012; Satomoto et al, 2009; Xie et al, 2020; Yu et al, 2020). In neonatal rodents, exposure to sevoflurane causes a transient increase in neuronal activity, rapid changes of dendritic spine density, and elevation of tau protein phosphorylation and interleukin‐6 expression in the brain (Dong et al, 2021; Lu et al, 2017; Tao et al, 2014; Yang et al, 2020; Yu et al, 2020; Zhang et al, 2020). Compared with younger adults, anesthesia induces greater delirium‐like behavior in older animals (Kilicaslan et al, 2013; Liufu et al, 2020; Wiklund et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of unfolded protein response prevents post‐anesthesia neuronal hyperactivity and synapse loss in aged mice

Chen

Gupta

et al. 2022

Aging Cell

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Delirium is the most common postoperative complication in older patients after prolonged anesthesia and surgery and is associated with accelerated cognitive decline and dementia. The neuronal pathogenesis of postoperative delirium is largely unknown. The unfolded protein response (UPR) is an adaptive reaction of cells to perturbations in endoplasmic reticulum function. Dysregulation of UPR has been implicated in a variety of diseases including Alzheimer's disease and related dementias. However, whether UPR plays a role in anesthesia-induced cognitive impairment remains unexplored. By performing in vivo calcium imaging in the mouse frontal cortex, we showed that exposure of aged mice to the inhalational anesthetic sevoflurane for 2 hours resulted in a marked elevation of neuronal activity during recovery, which lasted for at least 24 hours after the end of exposure. Concomitantly, sevoflurane anesthesia caused a prolonged increase in phosphorylation of PERK and eIF2α, the markers of UPR activation. Genetic deletion or pharmacological inhibition of PERK prevented neuronal hyperactivity and memory impairment induced by sevoflurane.Moreover, we showed that PERK suppression also reversed various molecular and synaptic changes induced by sevoflurane anesthesia, including alterations of synaptic NMDA receptors, tau protein phosphorylation, and dendritic spine loss. Together, these findings suggest that sevoflurane anesthesia causes abnormal UPR in the aged brain, which contributes to neuronal hyperactivity, synapse loss and cognitive decline

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“…Shiraishi and Ikeda [ 6 ] studied an uptake and biotransformation of sevoflurane in humans and concluded that, despite its relatively large minimum alveolar concentration (MAC), sevoflurane has a small uptake due to its low solubility, but the degradation rate is shown to be high, resulting in a higher serum fluoride concentration than for other halogenated anaesthetics. Most recently, Dong et al [ 7 ] assessed mice and neurons treated with anaesthetics sevoflurane and desflurane, and applied nanobeam-sensor technology, an ultrasensitive method, to measure tau/p-tau amounts. They showed that the sevoflurane induces tau trafficking from neurons to microglia.…”

Section: Introductionmentioning

confidence: 99%

Absolute Differential Cross-Sections for Elastic Electron Scattering from Sevoflurane Molecule in the Energy Range from 50–300 eV

Vukalović

Maljković

Blanco

et al. 2021

IJMS

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We report the results of the measurements and calculations of the absolute differential elastic electron scattering cross-sections (DCSs) from sevoflurane molecule (C4H3F7O). The experimental absolute DCSs for elastic electron scattering were obtained for the incident electron energies from 50 eV to 300 eV, and for scattering angles from 25° to 125° using a crossed electron/target beams setup and the relative flow technique for calibration to the absolute scale. For the calculations, we have used the IAM-SCAR+I method (independent atom model (IAM) applying the screened additivity rule (SCAR) with interference terms included (I)). The molecular cross-sections were obtained from the atomic data by using the SCAR procedure, incorporating interference term corrections, by summing all the relevant atomic amplitudes, including the phase coefficients. In this approach, we obtain the molecular differential scattering cross-section (DCS), which, integrated over the scattered electron angular range, gives the integral scattering cross-section (ICS). Calculated cross-sections agree very well with experimental results, in the whole energy and angular range.

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The anesthetic sevoflurane induces tau trafficking from neurons to microglia

Cited by 44 publications

References 79 publications

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

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

Inhibition of unfolded protein response prevents post‐anesthesia neuronal hyperactivity and synapse loss in aged mice

Absolute Differential Cross-Sections for Elastic Electron Scattering from Sevoflurane Molecule in the Energy Range from 50–300 eV

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