Interaction of Tau, IL-6 and mitochondria on synapse and cognition following sevoflurane anesthesia in young mice

Zhang, Jie; Dong, Yuanlin; Huang, Liyi; Xu, Xinjun; Liang, Feng; Soriano, Sulpicio G.; Zhang, Yiying; Xie, Zhongcong

doi:10.1016/j.bbih.2020.100133

Cited by 12 publications

(13 citation statements)

References 62 publications

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“…Thus, the combination of neurons and microglia was necessary to generate IL-6, which further supported the hypothesis that tau trafficking occurred from neurons to microglia, leading to IL-6 generation. Moreover, the sevoflurane conditioned culture medium of tau KO neurons did not increase IL-6 amount, further suggesting that the increase in IL-6 amounts was dependent on tau, consistent with the findings in previous studies 32 , 58 . Finally, sevoflurane-conditioned neuron culture medium induced activation of NF-kB signaling, which was attenuated by lithium (Supplemental Fig.…”

Section: Discussionsupporting

confidence: 91%

The anesthetic sevoflurane induces tau trafficking from neurons to microglia

et al. 2021

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Accumulation and spread of tau in Alzheimer’s disease and other tauopathies occur in a prion-like manner. However, the mechanisms and downstream consequences of tau trafficking remain largely unknown. We hypothesized that tau traffics from neurons to microglia via extracellular vesicles (EVs), leading to IL-6 generation and cognitive impairment. We assessed mice and neurons treated with anesthetics sevoflurane and desflurane, and applied nanobeam-sensor technology, an ultrasensitive method, to measure tau/p-tau amounts. Sevoflurane, but not desflurane, increased tau or p-tau amounts in blood, neuron culture medium, or EVs. Sevoflurane increased p-tau amounts in brain interstitial fluid. Microglia from tau knockout mice took up tau and p-tau when treated with sevoflurane-conditioned neuron culture medium, leading to IL-6 generation. Tau phosphorylation inhibitor lithium and EVs generation inhibitor GW4869 attenuated tau trafficking. GW4869 mitigated sevoflurane-induced cognitive impairment in mice. Thus, tau trafficking could occur from neurons to microglia to generate IL-6, leading to cognitive impairment.

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Section: Discussionsupporting

confidence: 91%

The anesthetic sevoflurane induces tau trafficking from neurons to microglia

et al. 2021

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“…DMSO, dimethyl sulfoxide. anesthesia-induced cognitive impairment in mice (Zhang et al, 2020). Idebenone is a synthetic analog of coenzyme Q (Rauchova et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

WS635 Attenuates the Anesthesia/Surgery-Induced Cognitive Impairment in Mice

Lin

Shen

et al. 2021

Front. Aging Neurosci.

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Anesthesia/surgery has been reported to be associated with perioperative neurocognitive disorder (PND) in patients and induces cognitive impairment in mice. Previous studies demonstrate cyclosporine A (CsA) attenuates the anesthesia/surgery-induced cognitive impairment in mice. However, CsA has immunosuppressive effects and may not be routinely used to prevent or treat PND in patients. WS635 is a nonimmunosuppressive CsA analog. We, therefore, set out to determine whether WS635 could mitigate the anesthesia/surgery-induced cognitive impairment in mice. We performed abdominal surgery under 1.4% isoflurane anesthesia (anesthesia/surgery) for 2 h in 9 month-old wild-type (WT) mice. We treated the mice with CsA (10 mg/kg) or different doses (13.2 mg/kg, 26.4 mg/kg and 52.8 mg/kg) of WS635 before and after the anesthesia/surgery. Barnes maze and fear conditioning system (FCS) were employed to evaluate the cognitive function in mice. We measured the amounts of postsynaptic density (PSD)-95, synaptophysin, and ATP in the hippocampus and cortex of the mice using western blot and ATP Colorimetric/Fluorometric Assay, respectively. We found that the treatment with 52.8 mg/kg, but not 13.2 mg/kg or 26.4 mg/kg, of WS635 attenuated the anesthesia/surgery-induced cognitive impairment in mice and the reductions in the amounts of PSD-95, synaptophysin, and ATP in the mice brain tissues. These results have established a system to study WS635 further and suggest that we need to perform more experiments to determine whether WS635 can ultimately be used as one of the interventions for PND in patients.

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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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Interaction of Tau, IL-6 and mitochondria on synapse and cognition following sevoflurane anesthesia in young mice

Cited by 12 publications

References 62 publications

The anesthetic sevoflurane induces tau trafficking from neurons to microglia

The anesthetic sevoflurane induces tau trafficking from neurons to microglia

WS635 Attenuates the Anesthesia/Surgery-Induced Cognitive Impairment in Mice

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

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