GSK-3在阿尔茨海默病样细胞骨架蛋白过度磷酸化中的作用(英文)  

Activation of Glycogen Synthase Kinase 3 Induces Alzheimer-like Hyperphosphorylation of Cytoskeleton Protein and Cell Damage

作　　者：余靖[1] 邓艳秋[1] 杨莹[1] 张家玉[1] 张业平[1] 张少华[1] 王建枝[1] 

机构地区：[1]华中科技大学同济医学院病理生理教研室,武汉430030

出　　处：《生物化学与生物物理进展》2004年第6期532-537,共6页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(3 992 5 0 12,3 0 170 2 2 1和 3 0 10 0 0 5 7);国家科技部基金(G9990 5 40 0 7);国家教育部基金(2 0 0 1 171)资助项目~~

摘　　要：神经原纤维缠结是阿尔茨海默病 (Alzheimerdisease ,AD)的特征性病理改变 .蛋白激酶和蛋白磷酸酯酶失衡可导致骨架蛋白的异常过度磷酸化 ,而异常过度磷酸化的tau和神经丝 (neurofilament,NF)是神经原纤维缠结的组成部分 .在众多激酶中 ,糖原合酶激酶 3(glycogensynthasekinase 3,GSK 3)可能是AD神经退行性变起重要作用 .为深入探讨GSK 3在AD样神经退行性变中的作用 ,以磷酯酰肌醇三磷酸激酶 (phosphatidylinositol 3 kinase ,PI3K)的特异性抑制剂渥曼青霉素 (wortmannin ,WT)处理野生型鼠成神经瘤细胞株 (wildtypemouseneuroblastomacelllines,N2awt) ,系统观察WT处理N2awt不同时间点 (1h、 3h、 6h)细胞代谢率、细胞形态、细胞骨架蛋白tau和NF的磷酸化状态改变以及细胞的命运 ,并分析了GSK 3活性与上述参数改变之间的相关性 .结果发现 :1μmol/LWT处理细胞 1h ,GSK 3活性与未经WT处理的对照组相比明显增高 ,并伴有Ser9磷酸化的GSK 3水平的降低 ;NF磷酸化程度增强 ,tau在Ser198/Ser199/Ser2 0 2位点的磷酸化增强 .1μmol/LWT处理细胞 3h ,GSK 3活性与对照组和处理 1h组相比明显下降 ,NF磷酸化程度较 1h降低 ,但仍高于正常水平 . 1μmol/LWT处理细胞 6h ,细胞形态、GSK 3活性、Ser9磷酸化形式的GSKNeurofibrillary tangles are the neuropathological hallmarks of Alzheimer disease (AD). Abnormally hyperphosphorylated tau and neurofilament (NF) are the components of neurofibrillary tangles. Hyperphosphorylation may be the result of an imbalanced regulation between protein kinases and protein phosphatases. Among the many kinases, glycogen synthase kinase-3(GSK-3) might be a key participator in neurodegeneration of AD. To investigate the role of GSK-3 on Alzheimer-like neurofibrillary degeneration, the wild type mouse neuroblastoma cell lines ( N2awt) were treated with wortmannin (WT), an inhibitor of phosphatidylinositol 3-kinase ( PI3K), and the effect of WT on cell metabolism, cell morphology, cell apoptosis, phosphorylation of NF and tau were detected, as well as the relationship between the alternations of these parameters and GSK-3 activity. It was found ( 1) that treatment of the cell with 1 mumol/L WT led to a transient ( at 1 h) activation of GSK-3 with a concurrent increase in phosphorylation of NF and tau. At 3 h, the activity of GSK-3 was decreased and the hyperphosphorylation of NF was partially restored. ( 2) that WT decreased the cell metabolism detected by MTT assay in a dose dependent manner. ( 3) that treatment of the cell with 1 mumol/L WT for I It or for 3h induced retraction of cell processes. (4) that no typical apoptotic damage was seen by transient stimulation of GSK-3 activity. It is suggested that transit overactivation of GSK-3 led to Alzheimer-like hyperphosphorylation of cytoskeleton protein and impairment in cell viability.

关 键 词：阿尔茨海默病 渥曼青霉素 糖原合酶激酶-3 神经细丝 磷酸化 

分 类 号：R745.7[医药卫生—神经病学与精神病学] Q513[医药卫生—临床医学]