脑胰岛素信号在阿尔兹海默症模型小鼠渐进过程中的改变

Brain insulin signaling pathway and glucose homeostasis in APP/SP1 transgenic mice models of AD

目的:探讨阿尔兹海默症(Alzheimer’s disease,AD)形成过程中脑胰岛素信号及葡萄糖转运体(glucose transporters,GLUTs)表达的改变,为AD早期诊断提供依据。方法:借助APP/PS1转基因AD模型小鼠,运用Western blot检测该模型鼠皮层和海马区域胰岛素信号通路相关蛋白的表达。结果:与对照组相比,AD模型鼠在3月龄时,表现为脑胰岛素信号应激性激活,下游AKT/GSK3β等胰岛素信号分子磷酸化水平升高,而GLUTs此时表达变化不明显;5月龄时,该模型表现为脑胰岛素信号磷酸化水平显著下降,其下游AKT/GSK3β等信号分子磷酸化水平表达下调,同时观察到海马中GLUT3、GLUT4表达下调,AD病理性蛋白(APP)、Tau蛋白磷酸化水平显著增加。结论:胰岛素信号紊乱和葡萄糖转运体在AD形成过程中发生紊乱,且随年龄增长,具有紊乱加剧的趋势。

Objective:This study was designed to explore the brain insulin signaling and the expression of glucose transporters(GLUTs)in APP/SP1 transgenic Alzheimer’s disease(AD)mice,it may provide the evidence for the early diagnosis of AD. Methods:Western blot was used to detect the expressions of insulin-signaling pathway related proteins in the cortex and hippocampus of the APP/PS1 transgenic AD model mice. Results:Our results showed that in the 3-month-old mice,brain insulin signaling was irritably activated,and the phosphorylation level of downstream AKT/GSK3β and other insulin signaling molecules increased,while the expression of GLUTs did not change significantly at this time. However,in the 5-month-old mice,it showed that the phosphorylation level of the brain insulin signal decreased significantly,and the phosphorylation level of its downstream AKT/GSK3β and other signaling molecules was down-regulated. At the same time,down-regulated expression of GLUT3 and GLUT4 was observed in the hippocampus,and the level of Tau protein phosphorylation(p-tau)was significantly increased. Conclusion:Our results confirmed that in APP/PS1 transgenic mice,brain insulin signaling pathway and glucose homeostasis were significantly disrupted in the process of AD formation,and the impairments increase with age.