解剖学报

解剖学报 ›› 2013, Vol. 44 ›› Issue (4 ): 451-455.doi: 10.3969/j.issn.0529-1356.2013.04.002

• 神经生物学 • 上一篇    下一篇

敲除淀粉样前体蛋白基因促进铝诱导的小鼠认知障碍损伤

王冬梅1,2  袁树民2  张旭2  张连峰2*    

  1. 1.河南科技大学医学院病原生物学教研室，河南 洛阳 471003; 2.中国医学科学院北京协和医学院医学实验动物研究所 卫生部人类疾病比较
        医学重点实验室，北京 100021
  • 收稿日期:2012-11-22 修回日期:2013-05-20 出版日期:2013-08-06 发布日期:2013-09-04
  • 通讯作者: 王冬梅 E-mail:wdmzgadyx@163.com
  • 基金资助:

    国家科技支撑计划课题(2012BA139B02)和国家“重大新药创制”科技重大专项课题（课题编号2011ZX09307-302

Gene knockout of amyloid precursor protein promotes aluminum-induced cognitive impairment in mice

WANG Dong-mei 1,2  YUAN Shu-min2  ZHANG Xu2  ZHANG Lian-feng2   

  1. 1. Department of Microbiology, Henan University of Science and Technology, Henan Luoyang 471000, China;2. Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Beijing 100021，China
  • Received:2012-11-22 Revised:2013-05-20 Online:2013-08-06 Published:2013-09-04

摘要：

目的 淀粉样前体蛋白(APP)基因是与痴呆症发生发展相关的重要基因，利用APP基因敲除小鼠探讨铝诱导的认知障碍损伤，及APP对中
毒性认知障碍损伤的作用。方法 3月龄同窝阴性小鼠分为野生对照组（WT）和铝处理组（WT+Al），APP敲除小鼠分为模型对照组（APP-/- ）和
模型处理组（APP-/- +Al），每组10只。铝处理组在粮食中加入相应剂量的乳酸铝，同窝阴性小鼠和APP-/-小鼠给予常规鼠粮作为对照，乳酸
铝处理8周后进行水迷宫实验。HE染色观察小鼠脑组织神经病理改变；Western blotting检测糖原合成激酶3β(GSK-3β)和Caspase-3的活性变
化。结果 与WT相比，WT+Al小鼠在原平台区域停留时间和穿越原平台区域次数减少了28.1%和18.8%，而APP-/- +Al小鼠在原平台区域停留时间
和穿越原平台区域次数减少了44.1%和51%。Western blotting显示，WT+Al小鼠和APP-/-+Al小鼠脑组织中p-GSK-3β分别减少了17.4%和46.4%。结论 APP基因敲除促进铝诱导的神经毒性和学习记忆损伤。APP基因敲除导致GSK-3β的磷酸化水平降低、活性增高。由于GSK-3β活性增加对痴呆症具有促进作用，推测APP通过抑制GSK-3β活性在痴呆症发生过程中发挥保护效应。

关键词: 淀粉样前体蛋白, 铝, 水迷宫, 认知障, 糖原合成激酶3, 小鼠

Abstract:

Objective Amyloid precursor protein (APP) is involved in dementia, however, little is known about its role in the development of dementia. The APP knockout mice were used to investigate the effects of amyloid precursor protein on
aluminum-induced cognitive impairment in mice. Methods  APP knockout mice and the littermates of no-negative mice aged 3 months were selected randomly and performed Morris water-maze tests after administration for 8 weeks. Aluminum was administrated in the diet. One group of APP knockout mice was used for vehicle group. One group of the littermates of no-negative mice was used as normal control (WT). The pathological changes in brain were detected by HE staining. The activities of glycogen synthase kinase 3β(GSK-3β)and Caspase-3 were also examined by Western blotting.  Results Compared with WT mice, Al-treated WT mice exhibited a decrease in the target-quadrant abidance by 28.1% and the crossing-target number by 18.8% in the probe test; APP knockout mice administrated showed a significant decrease in the target-quadrant abidance by 44.1% and the crossing-target number by 51% in the probe test. Compared with that of WT mice, the level of p-GSK-3β was decreased by 17.4% in Al-treated WT mice and by 46.4% in Al-treated APP knockout mice. Conclusion Gene knockout of APP promotes aluminum-induced neurotoxicity and cognitive impairment in mice. APP knockout leads to a significant increase of the activity of GSK-3β, which can accelerate the processing of dementia. Thus the protective effect of APP may be through inhibiting the activity of GSK-3β.

Key words: Amyloid ecursor protein, Aluminum, Morris water maze, Cognitive impairment, Glycogen synthase kinase 3β, Mouse