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 (21): 1938-1947.doi: 10.3969/j.issn.1673-5374.2013.21.002

• 原著:退行性病与再生 • 上一篇    下一篇

谁能成为阻止阿尔茨海默病进程的新靶点？

  

  • 收稿日期:2013-04-06 修回日期:2013-06-18 出版日期:2013-07-25 发布日期:2013-07-25

What is the new target inhibiting the progression of Alzheimer’s disease?

Lin Zhang1, Jing Yang2, Yunpeng Cao1   

  1. 1 Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
    2 Provincial Key Laboratory of Cardiovascular and Cerebrovascular Drug Basic Research, Liaoning Medical University, Jinzhou 121001, Liaoning Province, China
  • Received:2013-04-06 Revised:2013-06-18 Online:2013-07-25 Published:2013-07-25
  • Contact: Yunpeng Cao, Professor, Doctoral supervisor, Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China, ypengcao@yahoo.com.
  • About author:Lin Zhang, Studying for doctorate, Associate chief physician.

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摘要：

在阿尔茨海默病发病早期阶段，谁可能成为阻止其进程中的一个新靶点。鉴于此，实验观察了纹状体富集的酪氨酸磷酸酶61在具有空间学习记忆缺损的12月龄Tg-APPswe/PSEN1dE9双转基因小鼠脑组织的中表达。免疫组织化学结果发现，Tg-APPswe/PSEN1dE9双转基因鼠大脑皮质和海马中纹状体富集的酪氨酸磷酸酶61的蛋白表达显著增加，磷酸化N-甲基-D-天门冬氨酸受体2B表达明显减少。进一步用β-淀粉样肽1-42处理体外培养的C57BL/6小鼠皮质神经元建立阿尔茨海默病细胞模型。Western blot检测显示，采用N-甲基-D-天门冬氨酸受体拮抗剂AP5可显著抑制阿尔茨海默病细胞模型Aβ1-42诱导的纹状体富集的酪氨酸磷酸酶61的活性增强，而且细胞中Tyr1472位点的磷酸化N-甲基-D-天门冬氨酸受体2B蛋白表达降低，将纹状体富集的酪氨酸磷酸酶61 RNA干扰后N-甲基-D-天门冬氨酸受体2B磷酸化表达增加。结果说明，纹状体富集的酪氨酸磷酸酶61可扰乱N-甲基-D-天门冬氨酸受体转运过程，可能阻止阿尔茨海默病学习记忆障碍的进展。纹状体富集的酪氨酸磷酸酶61可能为阻止阿尔茨海默病进程的新靶点。

关键词: 神经再生, 脑损伤, 神经退行性变, 阿尔茨海默病, 纹状体富集的酪氨酸磷酸酶61, β-淀粉样肽, N-甲基-D-天门冬氨酸受体, N-甲基-D-天门冬氨酸受体2B亚单位, RNA干扰, 免疫组织化学, Western blot

Abstract:

To stop the progression of Alzheimer’s disease in the early stage, it is necessary to identify new therapeutic targets. We examined striatal-enriched phosphatase 61 expression in the brain tissues of 12-month-old APPswe/PSEN1dE9 transgenic mice. Immunohistochemistry showed that stria-tal-enriched phosphatase 61 protein expression was significantly increased but phosphorylated N-methyl-D-aspartate receptor 2B levels were significantly decreased in the cortex and hippocam-pus of APPswe/PSEN1dE9 transgenic mice. Western blotting of a cell model of Alzheimer’s disease consisting of amyloid-beta peptide (1–42)-treated C57BL/6 mouse cortical neurons in vitro showed that valeric acid (AP5), an N-methyl-D-aspartate receptor antagonist, significantly inhibited amyloid- beta 1–42-induced increased activity of striatal-enriched phosphatase 61. In addition, the phos-phorylation of N-methyl-D-aspartate receptor 2B at Tyr1472 was impaired in amyloid-beta 1–42-treated cortical neurons, but knockdown of striatal-enriched phosphatase 61 enhanced the phosphorylation of N-methyl-D-aspartate receptor 2B. Collectively, these findings indicate that stri-atal-enriched phosphatase 61 can disturb N-methyl-D-aspartate receptor transport and inhibit the progression of learning and study disturbances induced by Alzheimer’s disease. Thus, stria-tal-enriched phosphatase 61 may represent a new target for inhibiting the progression of Alz-heimer’s disease.

Key words: neural regeneration, brain injury, neurodegeneration, Alzheimer’s disease, striatal-enriched phos-phatase 61, amyloid-beta peptide, N-methyl-D-aspartate receptor, GluN2B, RNA interference, im-munohistochemistry, western blot, neuroregeneration