罗格列酮调节IDE和GSK-3β的活性改善AD动物模型的认知能力

Rosiglitazone resecues memory impairment in Alzheimer’rats:mechanisms involvingregulation of insulin-degrading enzyme and GSK-3β

摘要:

目的：本文旨在研究作为胰岛素增敏剂的PPARγ激动剂—罗格列酮对AD动物模型的认知水平、β淀粉样蛋白(Amyloid β-peptide,Aβ)和Tau的影响,并探讨其改善AD模型认知能力的可能机制。方法：通过侧脑室(intracerebroventricular,ICV)注射链脲佐菌素(streptozotocin,STZ)建立AD动物模型,并用罗格列酮处理动物,第1次手术后21天用Morris水迷宫检测动物的学习和记忆水平；采用western-blot检测胰岛素降解酶(insulin-degrading enzyme,IDE),糖原合成酶激酶-3β(glycogen synthase kinese-3β,GSK-3β),磷酸化糖原合成酶激酶-3β(pGSK-3β),Tau,磷酸化Tau(pTau)的表达；通过免疫组化检测Aβ40和Aβ42在大脑的沉积。结果：Morris水迷宫结果显示罗格列酮可以明显改善AD大鼠的认知能力(p<0.05)；western-blot结果显示罗格列酮能增加IDE的表达、降低GSK-3β的活性、减少Tau的磷酸化水平(p<0.05)；免疫组化结果显示罗格列酮处理的大鼠,其大脑皮质Aβ40和Aβ42均明显减少。结论：罗格列酮可以明显改善AD动物的认知能力、Aβ的沉积和Tau的磷酸化,机制可能与其调节胰岛素信号通路相关的IDE和GSK-3β的表达有关。

Abstract:

Objective:To investigate the effect of peroxisome proliferator-activated receptor γ(PPARγ)agonist- Rosiglitazone(RTZ) on the cognition, Aβand Tau in the AD rats and explore its potential mechanisms involving attenuate learning and memory deficits.Methods: Rosiglitazone was administered in the rats which were treated with intracerebroventricular (ICV) streptozotocin (STZ) induced dementia model. On the 21st day from 1st STZ injection, spatial learning and memory of rats were tested in Morris water maze.The expression of IDE, glycogen synthase kinese-3β(GSK-3β),phospho-GSK-3β(pGSK-3β),Tau and phospho-tau(pTau) were measured by western-blot. Amyloid β-peptide(Aβ)40 and 42 levels in the brain of the AD rats were tested by immunohistochemistry.Results: AD rats administered rosiglitazone exhibited better spatial learning and memory abilities and had lower Aβlevels than untreated AD rats(p<0.05). Rosiglitazone attenuated reduction in insulin-degrading enzyme and reduced GSK-3β activity(p<0.05).Conclusion: RTZ-mediated cognitive improvement of AD rats does correlate with the expression of IDE and GSK-3β.