α-分泌酶在自主运动调节APP/PS1转基因小鼠海马APP与Aβ42中的作用研究

Research on Effect ofα-secretase on Regulating Hippocampal APP and Aβ42 in APP/PS1 Transgenic Mice of Alzheimer's disease after Voluntary Wheel Running

目的:探讨α-分泌酶在16周自主跑轮运动调节APP/PS1转基因小鼠海马APP水解与Aβ42生成中的作用。方法:24只C57系APP/PS1转基因小鼠,随机分为自主跑轮运动组(TE,n=12)和对照组(TC,n=12);同时选取C57系野生型小鼠24只,随机分为自主跑轮运动组(E,n=12)和对照组(C,n=12)。TE组和E组小鼠从3月龄开始,除给予正常饮食、饮水外,给予16周的自主跑轮运动,TC组和C组小鼠给予正常饮食、饮水,不运动。采用实时荧光定量RT-PCR实验检测各组小鼠海马α-分泌酶家族的3种主要成员ADAM9、ADAM10和ADAM17mRNA表达水平,采用Western Blot实验检测各组小鼠海马APP、ADAM10和Aβ42蛋白表达水平。结果:1)16周的自主跑轮运动极显著性上调了APP/PS1转基因小鼠海马ADAM10mRNA表达水平(P<0.01),同时显著性上调了转基因小鼠海马ADAM10蛋白表达水平(P<0.05);2)16周的自主跑轮运动显著上调了APP/PS1转基因小鼠海马ADAM17 mRNA表达水平(P<0.05);3)16周的自主跑轮运动显著性下调了APP/PS1转基因小鼠海马APP(P<0.05)和Aβ42(P<0.05)的蛋白表达水平。结论:16周的自主跑轮运动可通过促进APP/PS1转基因小鼠海马α-分泌酶基因表达进而降低转基因小鼠海马APP的水平,并抑制APP水解产生Aβ42的水平。

Objective：To observe the effect ofα-secretase on the hippocampal APP cleaving and Aβ42deposition in transgenic mice of Alzheimer＇s disease（AD）after 16 weeks voluntary wheel running.Methods：24 male APP/PS1 transgenic mice of line C57 that expresses human mutant APP and PS1 in the brain were chosen and divided into wheel running group（TE,n=12）and control group（TC,n=12）.Meanwhile,24 male wild-type mice in line C57 were chose and divided into wheel running group（E,n=12）and control group（C,n=12）.Mice in group TE and group E were subjected to wheel running with ad libitum access to food and water for 16 weeks from 3 months of age.Mice in group TC and group C were subjected to food and water ad libitum,without exercise.Real-time RT-PCR was used to detect mRNA level of the main member ofα-secretase,ADAM9,ADAM10 and ADAM17.Western blot was used to detect protein level of APP,ADAM10 and Aβ42.Results：（1）16weeks wheel running significantly up-regulated the expression of ADAM10 mRNA（P〈0.01）and ADAM10protein（P〈0.05）in the hippocampus of APP/PS1 transgenic mice.（2）16weeks wheel running significantly up-regulated the expression of ADAM17 mRNA（P〈0.05）in the hippocampus of APP/PS1 transgenic mice.（3）16 weeks wheel running significantly decreased the protein expression of APP（P〈0.05）and Aβ42（P〈0.05）in the hippocampus of APP/PS1 transgenic mice.Conclusion：16weeks wheel running decreased the level of APP and its production Aβ42by promoting the gene expression ofα-secretase in the hippocampus of APP/PS1 transgenic mice.