Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia
Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia
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DOI：
10.1096/fj.08-122424
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发表时间：
2009-08-01
期刊：
影响因子：
4.8
通讯作者：
Duff, Karen E.
中科院分区：
文献类型：
--
作者：
Planel, Emmanuel;Bretteville, Alexis;Duff, Karen E.
阿尔茨海默病和其他tau蛋白病的特征在于存在由过度磷酸化的不溶性tau蛋白组成的细胞内神经元缠结。全身麻醉已被证明与阿尔茨海默病的风险增加有关，我们以前已经证明麻醉诱导体温过低，这导致小鼠大脑中明显的tau蛋白过度磷酸化，无论使用何种麻醉剂。为了研究麻醉是否会增加病理性tau蛋白形成的长期风险，我们将tau蛋白病小鼠模型暴露于麻醉，并在两个时间点（麻醉期间或暴露后1周）监测结果。我们发现，在临床相关剂量下暴露于异氟烷导致磷酸化tau水平升高，tau的不溶性、聚集形式增加，以及tau从微管上脱离。此外，分布在神经元和细胞体中的磷酸化tau水平增加。有趣的是，麻醉后1周，不溶性tau水平增加，这表明麻醉会加速大脑的变化，从而引发tau蛋白病的后期发展。总的来说，我们的研究结果表明，麻醉诱导的低温可能导致体内tau病理的加速，这可能对早期或明显的神经系统缠结病理的患者具有重要的临床意义。Planel，E.，Bretteville，A.，刘，L.，维拉格湖，Du，A. L.，余，W.是的，Dickson，D. W.，惠廷顿河一、Duff，K. E.麻醉后tau蛋白病小鼠模型中神经病理学的加速和持续。FASEB J. 23，2595-2604（2009）
Alzheimer's disease and other tauopathies are characterized by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated, insoluble tau. General anesthesia has been shown to be associated with increased risk of Alzheimer's disease, and we have previously demonstrated that anesthesia induces hypothermia, which leads to overt tau hyperphosphorylation in the brain of mice regardless of the anesthetic used. To investigate whether anesthesia enhances the long-term risk of developing pathological forms of tau, we exposed a mouse model with tauopathy to anesthesia and monitored the outcome at two time points-during anesthesia, or 1 wk after exposure. We found that exposure to isoflurane at clinically relevant doses led to increased levels of phospho-tau, increased insoluble, aggregated forms of tau, and detachment of tau from microtubules. Furthermore, levels of phospho-tau distributed in the neuropil, as well as in cell bodies increased. Interestingly, the level of insoluble tau was increased 1 wk following anesthesia, suggesting that anesthesia precipitates changes in the brain that provoke the later development of tauopathy. Overall, our results suggest that anesthesia-induced hypothermia could lead to an acceleration of tau pathology in vivo that could have significant clinical implications for patients with early stage, or overt neurofibrillary tangle pathology.-Planel, E., Bretteville, A., Liu, L., Virag, L., Du, A. L., Yu, W. Y., Dickson, D. W., Whittington, R. A., Duff, K. E. Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia. FASEB J. 23, 2595-2604 ( 2009)