罗格列酮调节IDE和GSK-3β的活性改善阿尔茨海默病动物认知能力

Rosiglitazone rescues memory impairment in Alzheimer'rats:mechanisms involving regulation of insulin-degrading enzyme and glycogen synthase kinese-3β

目的:研究作为胰岛素增敏剂的过氧化物酶体增殖因子活化受体γ(peroxisome proliferator-activated receptorsγ,PPARγ)激动剂-罗格列酮对阿尔茨海默病(Alzheimer’s disease,AD)动物模型的认知水平、β淀粉样蛋白(amyloidβ-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:通过侧脑室注射链脲佐菌素建立AD动物模型,并用罗格列酮处理动物,第1次手术后21 d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 kinase-3β,GSK-3β)、磷酸化糖原合成酶激酶-3β(pGSK-3β)、Tau、磷酸化Tau(phosphoTau,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<0.001);Western blot结果显示罗格列酮能增加IDE的表达(P=0.028)、降低GSK-3β的活性(P=0.012)、减少Tau的磷酸化水平(P=0.001);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的沉积量均较模型组减少。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。

Objective：To investigate the effects of peroxisome proliferator-activated receptor γ（PPARγ） agonist-rosiglitazone（RTZ） on the cognition,amyloid β-peptide（Aβ） and Tau in the Alzheimer＇s disease（AD） rats and to explore its potential mechanisms of attenuating learning and memory deficits.Methods：Dementia model was established by treating rats with intracerebroventricular streptozotocin injection.RTZ was administered to rats in dementia model.On the 21st d from the 1st STZ injection,spatial learning and memory of rats were tested in Morris water maze.Expressions of insulin-degrading enzyme（IDE）,glycogen synthase kinase-3β（GSK-3β）,phospho-GSK-3β（pGSK-3β）,Tau and phospho-Tau（pTau） were measured by Western blot.Aβ40 and Aβ42 levels in the brain of AD rats were tested by immunohistochemistry.Results：AD rats administrating RTZ exhibited better spatial learning and memory abilities（P0.001） and had lower Aβ levels than untreated AD rats.Western blot demonstrated that RTZ decreased IDE expression（P=0.028）,GSK-3β activity（P=0.012） and pTau level（P=0.001）.Immunohistochemical results demonstrated that RTZ reduced Aβ40 and Aβ42 levels in the cerebral cortex.Conclusions：RTZ-mediated cognitive improvement of AD rats does correlate with the expression of IDE and GSK-3β.