麻醉剂七氟醚诱导 tau 蛋白从神经元向小胶质细胞转运。
The anesthetic sevoflurane induces tau trafficking from neurons to microglia.
机构信息
Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Department of Anesthesiology, the Second Hospital of Hebei Medical University, Shijiazhuang, P.R. China.
出版信息
Commun Biol. 2021 May 12;4(1):560. doi: 10.1038/s42003-021-02047-8.
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.
在阿尔茨海默病和其他神经tau 病中，tau 的积累和扩散以类朊病毒的方式发生。然而，tau 运输的机制和下游后果在很大程度上仍是未知的。我们假设 tau 通过细胞外囊泡 (EVs) 从神经元转运到小胶质细胞，导致 IL-6 的产生和认知障碍。我们评估了用麻醉剂七氟醚和地氟醚处理的小鼠和神经元，并应用纳米束传感器技术（一种超灵敏的方法）来测量 tau/p-tau 的含量。七氟醚，但不是地氟醚，增加了血液、神经元培养液或 EVs 中的 tau 或 p-tau 含量。七氟醚增加了脑间质液中的 p-tau 含量。用七氟醚处理的神经元培养物处理后，tau 敲除小鼠的小胶质细胞摄取了 tau 和 p-tau，导致 IL-6 的产生。tau 磷酸化抑制剂锂和 EVs 生成抑制剂 GW4869 减弱了 tau 的运输。GW4869 减轻了七氟醚诱导的小鼠认知障碍。因此，tau 从神经元转运到小胶质细胞以产生 IL-6，导致认知障碍。
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