中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2013, Vol. 8 ›› Issue (34): 3173-3182.doi: 10.3969/j.issn.1673-5374.2013.34.001

• 原著:脑损伤修复保护与再生 •    下一篇

短暂性脑缺血多个时间点tau蛋白的磷酸化

  

  • 收稿日期:2013-08-30 修回日期:2013-11-20 出版日期:2013-12-05 发布日期:2013-12-05
  • 基金资助:

    基金项目：国家高技术研究发展计划 （"863"计划，2012AA020905），国家自然科学基金/香港研究资助局联合研究计划（81161160570），国家自然科学基金（81171143），清华-裕元医学科学基金。

Phosphorylation of tau protein over time in rats subjected to transient brain ischemia

Bo Song1, 2, Qiang Ao1, 3, Zhen Wang3, Weiqiang Liu3, Ying Niu2, Qin Shen4, Huancong Zuo1, Xiufang Zhang2, Yandao Gong2   

  1. 1 Institute of Neurology Disorders, Yuquan Hospital, Tsinghua University, Beijing 100049, China
    2 State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China
    3 Center for Advanced Materials and Biotechnology, Research Institute of Tsinghua University in Shenzhen, Shenzhen High-Tech Industrial Estate, Shenzhen 518057, China
    4Medical School, Tsinghua University, Beijing 100084, China
  • Received:2013-08-30 Revised:2013-11-20 Online:2013-12-05 Published:2013-12-05
  • Contact: Qiang Ao, M.D., Associate professor, Institute of Neurology Disorders, Yuquan Hospital, Tsinghua University, Beijing 100049, China, aoqiang@tsinghua.edu.cn. Yandao Gong, Master, Professor, State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China, gongyd@tsinghua. edu.cn.
  • About author:Bo Song, M.D., Assistant researcher.
  • Supported by:

    This work was supported by the National High Technology Research and Development Program of China (863 Program), No. 2012AA020905; the Biological Industry Development Funds of Shenzhen, No. JC201005260093A; the National Natural Science Foundation of China/Research Grants Council Joint Research Scheme, No. 81161160570; the National Natural Science Foundation of China, No. 81171143; and the Tsinghua-Yue-Yuen Medical Sciences Fund.

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摘要：

以往的研究显示，短暂性脑缺血能够诱导微管相关蛋白tau发生超磷酸化。为了进一步揭示其内在机制，实验研究了脑缺血及再灌注过程中tau蛋白、糖原合酶激酶-3β和蛋白磷酸酶2A的相互作用。结果发现，在脑缺血过程中，tau蛋白发生脱磷酸化、糖原合酶激酶-3β活性升高、蛋白磷酸酶2A活性降低；再灌注以后，tau蛋白又发生超磷酸化，同时糖原合酶激酶-3β活性降低，而蛋白磷酸酶2A的活性仍较低。更重要的是，脑缺血过程中tau与蛋白磷酸酶2A结合增加，而再灌注过程中，糖原合酶激酶-3β与tau结合增加，同时蛋白磷酸酶2A与tau结合降低。可见在脑缺血及再灌注过程中，对tau蛋白的磷酸化状态起主导作用的是tau蛋白与糖原合酶激酶-3β和蛋白磷酸酶2A的相互作用，而不是糖原合酶激酶-3β和蛋白磷酸酶2A的活性。实验进一步应用糖原合酶激酶-3β抑制剂氯化锂对缺血再灌注大鼠进行干预，发现氯化锂通过调节tau蛋白与糖原合酶激酶-3β和蛋白磷酸酶2A的相互作用，进而影响tau蛋白的磷酸化状态，从而改善脑缺血大鼠的学习与记忆能力。提示氯化锂在短暂性脑缺血过程中的神经保护作用可能与其抑制tau蛋白磷酸化有关。

中国神经再生研究（英文版）杂志出版内容重点： 脑损伤；脊髓损伤；周围神经损伤；帕金森；神经影像；神经再生

关键词: 神经再生, 脑损伤, 脑缺血, 再灌注, 微管相关蛋白tau, 磷酸化, 糖原合酶激酶-3β, 蛋白磷酸酶2A, 氯化锂, 基金资助文章

Abstract:

Transient brain ischemia has been shown to induce hyperphosphorylation of the microtu-bule-associated protein tau. To further determine the mechanisms underlying these processes, we investigated the interaction between tau, glycogen synthase kinase (GSK)-3β and protein phos-phatase 2A. The results confirmed that tau protein was dephosphorylated during brain ischemia; in addition, the activity of GSK-3β was increased and the activity of protein phosphatase 2A was de-creased. After reperfusion, tau protein was hyperphosphorylated, the activity of GSK-3β was de-creased and the activity of protein phosphatase 2A remained low. Importantly, the interaction of tau with GSK-3β and protein phosphatase 2A was altered during ischemia and reperfusion. Lithium chloride could affect tau phosphorylation by regulating the interaction of tau with GSK-3β and pro-tein phosphatase 2A, and improve learning and memory ability of rats after transient brain ischemia. The present study demonstrated that it was the interaction of tau with GSK-3β and protein phos-phatase 2A, rather than their individual activities, that dominates the phosphorylation of tau in tran-sient brain ischemia. Hyperphosphorylated tau protein may play an important role in the evolution of brain injury in ischemic stroke. The neuroprotective effects of lithium chloride partly depend on the inhibition of tau phosphorylation during transient brain ischemia.

Key words: neural regeneration, brain injury, brain ischemia, reperfusion, microtubule-associated protein tau, phosphorylation, glycogen synthase kinase 3β, protein phosphatase 2A, lithium chloride, grants-supported paper, neuroregeneration