阿尔茨海默病大鼠海马N-甲基天冬氨酸受体和丝裂酶原激活蛋白激酶的表达

EXPRESSION OF MAPK AND NMDAR IN THE HIPPOCAMPUS OF ALZHEIMER RAT

目的探讨N甲基天冬氨酸受体(NMDAR)及丝裂酶原激活蛋白激酶(MAPK)在阿尔茨海默病(AD)发病中的变化及其可能机制。方法将β淀粉样肽(Aβ1～40)1μl(10g L)在立体定位仪下注入大鼠海马建立大鼠AD模型。2周后测水迷宫潜伏期、长时程增强(LTP)、原位杂交方法检测大鼠海马NMDAR mRNA的表达及免疫组织化学SABC法检测MAPK的蛋白表达,并应用显微图像分析系统对两者的表达进行分析。结果AD模型组Aβ注射2周后,水迷宫潜伏期与模型组术前及对照组相比显著延长(P<0.05);模型组刺激前后fEPSP斜率变化及高频刺激增加的幅值与对照组相比显著下降(P<0.01);模型组海马CA1区、CA3区NMDAR mRNA及MAPK蛋白的表达显著降低(P<0.05或P<0.01)。相关性分析表明,AD模型2周后LTP检测的结果与NMDAR mRNA的表达及MAPK的蛋白表达呈正相关。结论Aβ通过抑制MAPK信号通路和降低NMDA受体磷酸化状态,导致大鼠海马LTP降低和学习记忆功能减低,参与AD学习记忆障碍和痴呆形成。

Objective To investigate the changes of expression of N-methyl-D-aspartate receptor(NMDAR)and mitogen activated protein kinase(MAPK)in Alzheimer disease(AD)rat model. Methods AD rat model was established by injection of amyloid-beta protein 1-40 1μl(10 g/L)into hippocampus of rat.NMDAR-mRNA and MAPK protein were immunostained by in situ hybradization histochemistry and immunohistochemistry respectively.Learning and memory ability,LTP were determined by Morris water maze and electrophysiological methods respectively. Results The escape latent was prolongated in Alzheimer rats two weeks after injection of Aβ than in control rats and in rats before the injection of Aβ(P<0.05),indicating that learning and memory ability of Alzheimer rats was decreased compared with the control rats.The slope alteration of field-excitory postsynaptic potentiation(fEPSP)between pro-and-post-high-frequency stimulation(HFS)was decreased in Alzheimer rats than in controls(P<0.01).The augmented amplitude of fEPSP by HFS was lower in Alzheimer rats than that in controls.NMDAR-mRNA and MAPK immunoreactive positive neurons in areas CA1 and CA3 of hippocampus were remarkablely decreased in Alzheimer rats than in control rats.The results indicated that LTP was related to the expression of NMDAR and MAPK positively in Alzheimer rats.Conclusion Aβ caused the decreases of LTP and learning and memory ability by inhibiting MAPK signal pathway and lowering NMDAR phosphorylation was involved in the pathogenesis of Alzheimer disease.