去铁敏阻抑ob/ob小鼠海马脑区的Tau蛋白过度磷酸化

目的研究去铁敏(DFO)对ob/ob小鼠脑内Tau过度磷酸化的影响,以探讨铁沉积是否涉及糖尿病(DM)的神经病理。方法繁育12只6月龄ob/ob小鼠,随机分为DFO组和对照组(n=6),分别给予腹腔注射DFO(100 mg·kg^-1)或空白溶剂15d。采用免疫组织化学和Western blot方法,检测小鼠海马脑区的Tau蛋白磷酸化及其调控蛋白激酶和磷酸酶的表达变化;DAB增强的Perl’s染色检测海马铁离子的分布。结果DFO处理后,ob/ob小鼠海马脑区Tau蛋白无明显变化,而在Ser396和Thr231位点的磷酸化水平降低。相应地,DFO组小鼠脑内蛋白激酶GSK3β和CDK5的活性显著下调,磷酸酶PP2A及其活性上调。另外,DFO组小鼠海马脑区的铁染色强度减弱。结论DFO能够有效改善ob/ob小鼠海马脑区的Tau病理,为揭示铁参与DM诱发的神经病理提供了新证据。

Deferoxamine alleviates the abnormal Tau phosphorylation in the hippocampus of ob/ob mice

Objective To investigate the effects of deferoxamine(DFO)on Tau hyperphosphorylation in the brain of ob/ob mice,and to explore whether iron deposition is involved in the neuropathology of diabetes mellitus(DM).Methods 6-month-old ob/ob mice were used as DM models and randomly divided into vehicle-treated or DFO-treated group(100 mg·kg^-1 body weight),6 in each group.After injected intraperitoneally for 15 days,the expressions of Tau,phosphorylated Tau,protein kinases and phosphatase were detected by immunohistochemistry and Western blot.The distribution of iron ions in the hippocampus was detected by DAB enhanced Perl’s staining.Results After DFO treatment,the total amount of Tau protein in the hippocampus of ob/ob mice showed no significant changes,while phosphorylation at sites Ser396 and Thr231 decreased markedly.Accordingly,the activity of protein kinase GSK3βand CDK5 in DFO-treated mice was significantly down-regulated,and the activity of phosphatase PP2 A was up-regulated.In addition,the iron staining intensity in the hippocampal area of DFO treatment mice was decreased.Conclusion DFO can effectively improve Tau pathology in the brain of ob/ob mice,providing new evidence for revealing the role of iron in DM-induced neuropathology.