吡格列酮改善胰岛素抵抗大鼠脑组织Tau蛋白磷酸化水平

目的探讨胰岛素增敏剂吡格列酮(PIO)对胰岛素抵抗(IR)模型大鼠皮质Tau蛋白磷酸化水平的影响及可能的机制。方法选择Wistar大鼠46只,随机选20只分为对照组和PIO组,每组10只;另26只通过果糖喂养建立IR大鼠模型后,分为IR组和IR+PIO组,每组13只,采用免疫印迹法检测皮质Tau蛋白磷酸化、磷酸化磷脂酰肌醇3激酶(PI3K)、磷酸化蛋白激酶B(PKB)、糖原合成激酶-3β(GSK-3β)及GSK-3β位点中Ser9的磷酸化水平。结果与对照组比较,IR组大鼠皮质Tau蛋白磷酸化水平明显增高;磷酸化PI3K、磷酸化PKB和磷酸化GSK-3β蛋白表达明显降低(P<0.05,P<0.01);而PIO能显著抑制Tau蛋白磷酸化水平,上调磷酸化PI3K、磷酸化PKB和磷酸化GSK-3β的水平(P<0.05,P<0.01);各组GSK-3β差异无统计学意义(P>0.05)。结论 IR通过抑制PI3K-丝/苏氨酸蛋白激酶通路激活,促进GSK-3β活性上调,可能是引起大鼠海马Tau蛋白过度磷酸化的重要原因;PIO可能通过降低GSK-3β活性进而抑制Tau蛋白的过度磷酸化。

Pioglitazene blocks the phosphorylation of Tau protein in brain tissue of insulin-resistant rats

Objective To explore the effect of pioglitazene(PIO),an insulin-sensitizing agent,on Tau protein phosphorylation in cortex of insulin-resistant(IR) rats and the possible mechanism. Methods 20 Wistar rats were randomly selected from 46 and divided into control group and PIO group and the other 26 rats were divided into IR group and IR+PIO group after modeling.Western blot was performed to detect the phosphorylation of Tau-Serl99,Tau-Ser396 and the expression of phospho-PI3K,phospho-PKB,GSK-3β,and phospho-GSK-3β(Ser9).Results The phosphorylation of Tau-Serl99 and Tau-Ser396 in cortex of IR rats was increased significantly and the expression of phospho-PI3K and phospho-PKB was lower than in control group.Compared with control group,the expression of phospho-GSK-3βin IR group was significantly decreased.Pioglitazene could significantly inhibit phosphorylation of Tau-Serl99 and Tau-Ser396,but raise the expression of phospho-PI-3K,phospho-PKB and the expression of phospho-GSK-3β.There was no statistical difference in the expression of GSK-3βamong groups.Conclusion Insulin resistance could up-regulate the activity of GSK-3βthrough inhibiting PI3K-Akt/PKB pathway,an insulin signal transduction pathway in cell,that may be an important reason for excessive phosphorylation of Tau protein in rat hippocampus.Pioglitazene may depress the activity of GSK-3βby promoting phosphorylation of GSK-3β(Ser9),further inhibit excessive phosphorylation of Tau protein.