《中国康复理论与实践》

《中国康复理论与实践》 ›› 2009, Vol. 15 ›› Issue (08): 723-727.

• 基础研究 • 上一篇    下一篇

二苯乙烯苷对不同时程APP转基因拟痴呆小鼠脑内ERK蛋白表达及磷酸化的影响

张兰1,2;邢颖1;叶翠飞1;李林1;董奇2   

  1. 1.首都医科大学宣武医院药物研究室，教育部神经变性病学重点实验室，北京市 100053;2.北京师范大学认知神经科学与学习研究所，北京市 100875
  • 收稿日期:2009-06-12 出版日期:2009-08-01 发布日期:2009-08-01
  • 通讯作者: 李林

Effect of 2,3,5,4′-tetrahydroxy Stilbene-2-O-β-D-glucoside on Activation of ERK in APP Transgenic Model of Alzheimer's Disease

ZHANG Lan,XING Ying,YE Cui-fei,et al   

  1. Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China
  • Received:2009-06-12 Published:2009-08-01 Online:2009-08-01

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摘要： 目的 为探讨细胞信号转导异常在阿尔茨海默病(AD)的作用，以及中药有效成分二苯乙烯苷(TSG)防治AD的药理机制，观察不同时程APP转基因拟痴呆小鼠脑内ERK蛋白的表达和磷酸化改变，以及药物的干预作用。方法 拟AD动物模型为4～16月龄APP695V717I转基因小鼠。4月龄起灌胃给予TSG 6个月。另一批未处理的APP转基因小鼠饲养至10月龄开始灌胃给予TSG 6个月。同背景同月龄C57BL/6J小鼠为正常对照组。细胞外信号调节激酶1/2(ERK1/2)蛋白的表达和磷酸化改变检测应用Western blotting。结果 早期4月龄APP转基因小鼠海马/皮层被激活的磷酸化ERK1/2蛋白(p-ERK1/2)与对照组相比已明显降低；10月龄APP转基因小鼠皮层p-ERK蛋白表达进一步降低，而海马p-ERK蛋白表达与对照组相比虽显著降低但差异已明显减小；TSG各剂量组均能明显提高海马/皮层p-ERK蛋白表达；16月龄APP转基因小鼠海马/皮层p-ERK蛋白表达与对照组相比均明显升高，TSG给药组能一定程度地减少p-ERK蛋白表达的增高。总的ERK1/2蛋白表达在4、10、16月龄对照组、APP转基因模型组和各给药组小鼠脑内，均无明显变化。结论 ERK1/2作为MAPK信号转导通路的重要成分，其蛋白表达在不同时程APP695V717I转基因小鼠脑内无明显改变；但被激活的ERK1/2其磷酸化水平在APP转基因小鼠脑内明显改变，将影响信号转导功能，并进一步导致脑内功能障碍及病理损伤。TSG可调节p-ERK1/2至正常水平，对维持正常的细胞信号转导功能、防治AD等神经退行性疾病具有良好的应用前景。

关键词: 阿尔茨海默病, APP转基因小鼠, 细胞外信号调节激酶1/2(ERK1/2), 信号转导, 二苯乙烯苷

Abstract: Objective To investigate the deficit of extracellular-signal regulated kinase (ERK)1/2 activation in the different age of Alzheimer's disease (AD)-like animal model and the protective effect of 2,3,5,4′-tetrahydroxy stilbene-2-O-β-D-glucoside(TSG), which is the main component of Polygonum multiflorum, on ERK activation. Methods A generally accepted animal model of AD - PDAPPV717I transgenic (Tg) mouse was observed from 4 to 16 months old. Tg mice were randomly divided into 3 model groups(4, 10 and 16 months old mice)and TSG treated (at doses 120 and 240 μmol/kg/d) groups. TSG was administered to some Tg mice with an age range 4-10 months. In untreated 10 months old Tg mice, the TSG was administrated to those falling in the age range 10-16 months. For the control group we adopted the same age and background C57BL/6J mice. The ERK1/2 expression and phosphorylation were detected by Western blotting.Results In the 4-month-old PDAPPV717I Tg mice, phosphorylation of ERK1/2 decreased significantly in hippocampus and cortex compared with age matched control. In the 10-month-old Tg mice, decrease of ERK1/2 activation was aggravated in cortex but was less in hippocampus. The treatment of TSG at the doses of 120 and 240 μmol/kg for 6 months (from the age of 4 to 10 months) significantly up-regulated ERK1/2 activation in Tg mice. In the 16-month-old Tg mice, over-activation of ERK1/2 occurred in both hippocampus and cortex. The transgenic mice treated by TSG for 6 months (from the age of 10 months to 16 months) showed significant inhibition of over-activation of ERK1/2. Expression of total ERK1/2 showed no difference among control, Tg model and TSG treated groups.Conclusion PDAPPV717I transgenic mice with an age range from 4 to 16 months revealed the time-dependent deficit of ERK1/2 activation. TSG can bring the down or over activation of ERK1/2 into normal. Because ERK1/2 activation plays the crucial role in cellular signal transduction and learning-memory ability, TSG may have beneficial potential to the prevention and treatment of neurodegenerative diseases like AD.

Key words: Alzheimer's disease(AD), PDAPPV717I transgenic mice, extracellular-signal regulated kinase (ERK), signal transduction, tetrahydroxy stilbene glucoside