S14G-humanin对APP/PS1转基因小鼠认知功能和脑胰岛素抵抗的影响

Effects of S14G-humanin on cognitive function and hippocampal insulin resistance in APP/PSl transgenic mice

目的Humanin(HN)是从AD患者大脑提取的线性多肽,S14G-humanin(HNG)是其衍生物,HNG可通过减轻炎症反应、抑制氧化应激、改善神经突触功能、减少细胞凋亡等机制发挥神经保护作用。该文探讨HNG对痴呆模型小鼠脑胰岛素抵抗及认知的作用。方法APP/PSl转基因小鼠分为模型组(transgenic,Tg)及HNG治疗组(transgenic/HNG,Tg/HNG),对照组(control group,CG)选用同月龄C57BL/6J小鼠。Morris水迷宫实验评估小鼠的空间学习记忆能力;免疫组织化学方法检测IRS-1磷酸化产物IRS-1pSer636的表达;Western blot法检测小鼠海马胰岛素抵抗相关蛋白IRS-1、IRS-1pSer636、Akt、p-Akt的表达;ELISA法检测小鼠脑内Aβ1-42水平。结果与CG组比较,Tg组寻找平台的逃避潜伏期延长(P<0.05)、穿越原平台所在目的象限的次数减少(P<0.05),海马p-Akt表达降低、IRS-1pSer636表达升高(P<0.05);经HNG治疗后各异常指标均明显改善(P<0.05);各组总IRS-1、Akt蛋白表达差异无统计学意义(P>0.05)。结论HNG可减轻APP/PSl小鼠脑胰岛素抵抗、减少脑内Aβ沉积有关,从而改善空间学习记忆能力。

Aim To explore the effect of S14G-humanin(HNG),a derivative of a linear polypeptide extracted from the brains of AD patients,on alleviation of hippocampal insulin resistance in APP/PSl transgenic mice and its mechanisms.Methods Eight-month old APP/PS1 transgenic mice were randomly divided into two groups:contol group(CG)and HNG treatment group(Tg/HNG).C57BL/6J mice were utilized as control.Learning and memory were detected by Morris water maze test.The hippocampal IRS-1,IRS-1pSer636,Akt,p-AktSer473 and Aβ1-42 expression were detected by Western blot,immunohistochemical staining and Elisa.Results Compared with CG mice,Tg mice showed a marked prolongation of the escape latency in MWM test(P<0.05).Decreased p-AktSer473 expression and increased IRS-1pSer636 and Aβ1-42 were detected(P<0.05).HNG-treated mice showed significantly improvement in all these abnormal changes(P<0.05).Conclusions HNG treatment can improve the cognitive function,which may be attributed to ameliorated insulin resistance and reduced Aβplaques in hippocampi of APP/PSl transgenic mice.