慢性脑缺血导致tau蛋白发生超磷酸化及可能的机制  

The possible mechanism underlying tau hyperphosphorylation in rats subjected to chronic brain ischemia

作　　者：宋波[1] 敖强[2] 公衍道[1] 

机构地区：[1]清华大学生命科学学院,北京100084 [2]清华大学玉泉医院神经中心

出　　处：《中华临床医师杂志（电子版）》2013年第5期120-123,共4页Chinese Journal of Clinicians(Electronic Edition)

基　　金：国家自然科学基金(81171143;30971011);清华大学周大福医学研究专项基金;清华-裕元医学科学研究基金

摘　　要：目的研究大鼠慢性脑缺血过程中tau蛋白的磷酸化以及糖原合酶激酶-3β(GSK-3β)和蛋白磷酸酶2A(PP2A)的活性的变化。方法构建了大鼠三动脉结扎慢性脑缺血模型,通过免疫印迹的手段观察tau蛋白的磷酸化、GSK-3β和PP2A的活性,利用Morris水迷宫实验检测动物的学习与记忆能力,用组织学手段观察了大鼠海马神经元存活状况,同时研究了GSK-3β的抑制剂氯化锂对上述指标的影响。结果慢性脑缺血过程中,tau蛋白发生超磷酸化,GSK-3β的活性稍微降低,PP2A的活性大幅降低,动物学习与记忆能力显著下降,存活的海马神经元的数量大量减少。氯化锂能进一步抑制慢性脑缺血过程中GSK-3β的活性,增强PP2A的活性,降低tau蛋白的磷酸化,改善动物的学习与记忆能力,使海马神经元的数量显著增加。结论慢性脑缺血导致tau蛋白发生超磷酸化,GSK-3β和PP2A可能在其中起重要作用。超磷酸化的tau蛋白是慢性脑缺血导致脑损伤的一个重要因素。Objective To investigate the effects of chronic brain ischemia on the phosphorylation of tau protein and the activity of Glycogen synthase kinase 3β （GSK-3β） and protein phosphatase 2A （PP2A）.Methods Chronic brain ischemia was induced by three-vessel occlusion （3VO） in Sprague-Dawley （SD） rats.By immunoblot analysis,tau phosphorylation and the activity of GSK-3β and PP2A was examined.The learning and memory ability of rats was investigated by Morris water maze test.The number of hippocampal CA1 pyramidal cells was examined by Cresyl Violet stainning.In the meantime,lithium chloride （inhibitor of GSK-3β）was used to investigate above phenomenons.Results During chronic brain ischemia,tau protein was hyperphosphorylated.The activty of GSK-3β was modestly decreased.The activity of PP2A was heavily decreased.The learning and memory ability of rats was declined and the number of hippocampal CA1 pyramidal cells was fewer than sham control.Lithium chloride could further inhibit the activity of GSK-3β.The activity of PP2A was increased by lithium chloride,and the phosphorylation of tau protein was decreased by lithium chloride.The learning and memory ability of rats was improved by lithium chloride.The number of hippocampal CA1 pyramidal cells was increased after lithium chloride treatment.Conclusions Tau protein is hyperphosphorylated in chronic brain ischemia.GSK-3β and PP2A may involved in tau hyperphosphorylaion induced by chronic brain ischemia.Hyperphosphorylated tau protein may play an important role in the evolution of brain injury in chronic brain ischemia.

关 键 词：脑缺血 TAU蛋白质类 糖原合成酶激酶3 蛋白质磷酸酶2 氯化锂 

分 类 号：R743.3[医药卫生—神经病学与精神病学]