Modulation of murine Alzheimer pathogenesis and behavior by surgery.
Modulation of murine Alzheimer pathogenesis and behavior by surgery.
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DOI：
10.1097/sla.0b013e318269d623
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发表时间：
2013-03
影响因子：
9
通讯作者：
Eckenhoff MF
中科院分区：
文献类型：
--
作者：
Tang JX;Mardini F;Janik LS;Garrity ST;Li RQ;Bachlani G;Eckenhoff RG;Eckenhoff MF
先前的研究表明，麻醉剂暴露和阿尔茨海默病之间存在联系。由于很少单独使用麻醉剂，我们想知道是否手术可以进一步调节阿尔茨海默病。认知功能障碍发生在人类手术后。单独麻醉在老年野生型小鼠和大鼠中均产生认知能力下降，并且手术的添加在年轻成年野生型小鼠中产生短暂的下降。由于神经炎症已经被牵连，并发生在阿尔茨海默病的早期，我们假设与手术相关的神经炎症应激将加速阿尔茨海默病的进展。在地氟烷麻醉下，对症状前5-11月龄的三转基因阿尔茨海默病（3xTgAD）和C57 BL/6野生型小鼠进行盲肠结扎和切除。将手术动物与暴露于空气或单独地氟烷的年龄匹配的3xTgAD和WT小鼠进行比较。术后2周和13周采用Morris水迷宫评估大鼠的认知功能。用免疫组织化学、Luminex、ELISA或蛋白质印迹测定定量淀粉样蛋白和tau病理学以及炎症和突触标志物。与空气或地氟烷对照相比，接受手术的3xTgAD小鼠出现明显的认知障碍，并持续到手术后至少14周。与地氟烷单独给药相比，手术增强了小胶质细胞活化、淀粉样蛋白病和tau蛋白病。在WT小鼠中未检测到手术、麻醉或空气对照之间的差异。手术主要通过短暂激活神经炎症导致阿尔茨海默病发病机制的持久增加。
Previous research suggests a link between anesthetic exposure and Alzheimer’s disease exists. Since anesthetics are rarely given alone, we ask whether addition of surgery further modulates Alzheimer’s disease. Cognitive dysfunction occurs after surgery in humans. Anesthesia alone produces cognitive decline in both older wild-type mice and rats, and the addition of surgery produces transient decline in young adult wild type mice. Because neuroinflammation has been implicated, and occurs early in Alzheimer’s disease, we hypothesize that the neuroinflammatory stress associated with surgery will accelerate the progression of Alzheimer’s disease. Cecal ligation and excision was performed on pre-symptomatic 5–11 month-old triple-transgenic Alzheimer (3xTgAD) and C57BL/6 wild type mice under desflurane anesthesia. Surgery animals were compared to aged matched 3xTgAD and WT mice exposed to air or desflurane alone. Cognitive function was assessed via Morris water maze at 2 and 13 weeks post-operatively. Amyloid and tau pathology, as well as inflammation and synaptic markers were quantified with immunohistochemistry, Luminex, ELISA or western blot assays. A significant cognitive impairment in 3xTgAD mice that underwent surgery compared with air or desflurane controls, persisted to at least 14 weeks after surgery. Microglial activation, amyloidopathy and tauopathy were enhanced by surgery as compared to desflurane alone. No differences between surgery, anesthetic or air controls were detected in WT mice Surgery causes a durable increment in Alzheimer pathogenesis, primarily through a transient activation of neuroinflammation.