基于ANG/VEGF信号通路探讨有氧运动改善Aβ_(1~42)诱导AD大鼠认知功能的机制

The Mechanisms of Aerobic Exercise on Cognitive Impairment in Aβ_(1~42)-induced Rat Model of Alzheimer’s Disease Based on the ANG/VEGF Signaling Pathway

目的:探讨有氧运动通过调节血管抑制素(ANG)/血管内皮生长因子(VEGF)信号通路对Aβ_(1~42)诱导的AD大鼠模型认知功能障碍的影响。方法:36只健康雄性SD大鼠随机分成AD造模运动组、AD造模静息组、空白造模运动组、空白造模静息组,每组9只。其中对AD造模运动组、AD造模静息组的大鼠注射Aβ_(1~42)多肽制备AD模型,AD造模运动组、空白造模运动组在动物跑台上进行有氧运动。Morris水迷宫实验测试大鼠的空间学习和记忆能力,实时荧光定量PCR测量大鼠海马体HIF-1α、VEGF、VEGFR2、ANG mRNA的水平。结果:Morris水迷宫测试结果显示:AD造模静息组的逃避潜伏期(P=0.001)和游泳路线长度(P=0.009)均比空白造模静息组的长,但是在目标象限活动时间所占的百分比(P=0.002)比空白造模静息组的少,差异均有统计学意义;AD造模运动组的逃避潜伏期(P=0.007)和游泳路线长度(P=0.011)均比AD造模静息组的短,但是在目标象限活动时间所占的百分比(P=0.013)比AD造模静息组的多,差异均有统计学意义。实时荧光定量PCR检测结果显示:AD造模静息组HIF-1α(P=0.017)、VEGF(P<0.001)、VEGFR2(P<0.001)mRNA的水平均比空白造模静息组的低,但是ANG(P=0.012)mRNA的水平比空白造模静息组的高;AD造模运动组HIF-1α(P<0.001)、VEGF(P=0.024)、VEGFR2(P=0.011)mRNA的水平均比AD造模静息组的高,但是ANG(P=0.012)mRNA的水平比AD造模静息组的低,差异均有统计学意义。结论:Aβ_(1~42)诱导的AD大鼠模型空间学习和记忆能力受损,有氧运动可以使其得到一定程度的改善,同时有氧运动还可以降低AD大鼠模型ANG的水平,而ANG与VEGF信号通路的表达呈负相关。

Objective:To investigate the effects of aerobic exercise on cognitive impairment induced by Aβ_(1~42) in AD rats by regulating angiostatin(ANG)/vascular endothelial growth factor(VEGF)signaling pathway.Methods:36 healthy male SD rats were randomly divided into AD modeling exercise group,AD modeling rest group,blank modeling exercise group,and blank modeling rest group,with 9 rats in each group.Among them,rats in AD modeling exercise group and AD modeling rest group were injected with Aβ_(1~42) polypeptide to prepare AD model,and rats in AD modeling exercise group and blank modeling exercise group were aerobic on the animal treadmill.Morris water maze experiment tested the spatial learning and memory ability of rats,and real-time fluorescent quantitative PCR measured the levels of HIF-1α,VEGF,VEGFR2 and ANG mRNA in the rat hippocampus.Results:Morris water maze test results showed that the escape latency(P=0.001)and swimming route length(P=0.009)of the AD modeling rest group were longer than those of the blank modeling rest group,but the percentage of activity time in the target quadrant(P=0.002)was less than that of the blank modeling rest group,and the differences were statistically significant.The escape latency(P=0.007)and swimming route length(P=0.011)of the AD modeling exercise group were shorter than those of the AD modeling rest group,but the percentage of activity time in the target quadrant(P=0.013)was higher than that of the AD modeling rest group,and the differences were also statistically significant.The results of real-time fluorescence quantitative PCR showed that the levels of HIF-1α(P=0.017),VEGF(P<0.001)and VEGFR2(P<0.001)mRNA in the AD modeling rest group were lower than those in the blank modeling rest group,but the level of ANG(P=0.012)mRNA was higher than that in the blank modeling rest group.The levels of HIF-1α(P<0.001),VEGF(P=0.024),VEGFR2(P=0.011)mRNA in the AD modeling exercise group were higher than those in the AD modeling rest group,but the levels of ANG(P=0.012)mRNA were lower than those in the AD modeling rest group,and the differences were also statistically significant.Conclusion:Aβ_(1~42) induced spatial learning and memory impairment in AD rat model,aerobic exercise can improve it to a certain extent,and aerobic exercise can also reduce the level of ANG in AD rat model,and ANG is negatively correlated with the expression of VEGF signaling pathway.