七氟醚麻醉通过顺序的 tau 磷酸化诱导幼鼠认知功能障碍。
Sevoflurane anaesthesia induces cognitive impairment in young mice through sequential tau phosphorylation.
机构信息
Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA; Department of Anesthesiology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
出版信息
Br J Anaesth. 2023 Oct;131(4):726-738. doi: 10.1016/j.bja.2023.06.059. Epub 2023 Aug 1.
BACKGROUND
The volatile anaesthetic sevoflurane induces time (single or multiple exposures)-dependent effects on tau phosphorylation and cognitive function in young mice. The underlying mechanism for this remains largely undetermined.
METHODS
Mice received 3% sevoflurane for 0.5 h or 2 h daily for 3 days on postnatal day (P) 6, 9, and 12. Another group of mice received 3% sevoflurane for 0.5 h or 1.5 h (3 × 0.5) on P6. We investigated effects of sevoflurane anaesthesia on tau phosphorylation on P6 or P12 mice, on cognitive function from P31 to P37, and on protein interactions, using in vivo studies, in vitro phosphorylation assays, and nanobeam single-molecule level interactions in vitro.
RESULTS
An initial sevoflurane exposure induced CaMKIIα phosphorylation (132 [11]% vs 100 [6]%, P<0.01), leading to tau phosphorylation at serine 262 (164 [7]% vs 100 [26]%, P<0.01) and tau detachment from microtubules. Subsequent exposures to the sevoflurane induced GSK3β activation, which phosphorylated detached or free tau (tau phosphorylated at serine 262) at serine 202 and threonine 205, resulting in cognitive impairment in young mice. In vitro phosphorylation assays also demonstrated sequential tau phosphorylation. Nanobeam analysis of molecular interactions showed different interactions between tau or free tau and CaMKIIα or GSK3β, and between tau and tubulin at a single-molecule level.
CONCLUSIONS
Multiple exposures to sevoflurane can induce sequential tau phosphorylation, leading to cognitive impairment in young mice, highlighting the need to investigate the underlying mechanisms of anaesthesia-induced tau phosphorylation in developing brain.
背景
挥发性麻醉剂七氟醚可诱导年轻小鼠的 tau 磷酸化和认知功能出现时间（单次或多次暴露）依赖性变化。但其潜在机制仍未完全确定。
方法
在出生后第 6、9 和 12 天，每天给 3%七氟醚麻醉 0.5 或 2 小时，共 3 天。另一组小鼠在第 6 天接受 3%七氟醚麻醉 0.5 或 1.5 小时（3×0.5）。我们通过体内研究、体外磷酸化测定和纳米梁单分子水平的体外相互作用，研究了七氟醚麻醉对第 6 天或第 12 天小鼠 tau 磷酸化、第 31 至 37 天认知功能以及蛋白相互作用的影响。
结果
首次七氟醚暴露诱导 CaMKIIα 磷酸化（132[11]% vs 100[6]%，P<0.01），导致 tau 在丝氨酸 262 磷酸化（164[7]% vs 100[26]%，P<0.01）和 tau 从微管上脱离。随后暴露于七氟醚中会诱导 GSK3β 激活，磷酸化脱离或游离的 tau（tau 在丝氨酸 262 磷酸化）在丝氨酸 202 和苏氨酸 205 处，导致幼鼠认知功能障碍。体外磷酸化测定也证明了 tau 的顺序磷酸化。纳米梁分子相互作用分析表明，tau 或游离 tau 与 CaMKIIα 或 GSK3β 之间，以及 tau 与微管之间在单分子水平上存在不同的相互作用。
结论
多次暴露于七氟醚可诱导 tau 顺序磷酸化，导致幼鼠认知障碍，突出了需要研究麻醉诱导发育中大脑 tau 磷酸化的潜在机制。
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