Yang Sisi, Chen Zhe, Cao Ming, Li Renjie, Wang Zhigang, Zhang Muxun
Department of Geriatrics, Tongji Hospital Affiliated to The Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital Affiliated to The Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
Mol Med Rep. 2017 May;15(5):2588-2594. doi: 10.3892/mmr.2017.6342. Epub 2017 Mar 16.
Pioglitazone may have potential benefits as an alternative therapeutic treatment for patients with Alzheimer's disease (AD), particularly in individuals that also have comorbid diabetes; however, the mechanisms of action remain unclear. The present study aimed to explore the effects of pioglitazone on amyloid β, isoform 42 (Aβ42) deposition in rats with diet‑induced insulin resistance (IR). Diet‑induced IR model rats were established in the presence or absence of pioglitazone. Plasma glucose and insulin levels, and cerebrospinal fluid insulin levels were measured; in addition, hippocampal tissues were collected for immunohistochemical analysis of Aβ42 expression. The levels of insulin‑degrading enzyme (IDE) and peroxisome proliferator‑activated receptor γ (PPARγ) mRNA and protein expression were analyzed by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. In addition, the activation of glycogen synthase kinase 3β (GSK3β) induced by phosphatidylinositol 3‑kinase (PI3K) /protein kinase B (AKT) signaling was detected by western blotting. Results from the present study demonstrated that pioglitazone may enhance peripheral and brain insulin sensitivity in diet‑induced IR model rats. Treatment with pioglitazone ameliorated Aβ42 deposition in the hippocampus by increasing IDE and PPARγ expression. Notably, activation of the PI3K/AKT/GSK3β pathway was also demonstrated to serve a role in pioglitazone‑induced Aβ42 degradation, which was abrogated by the PPARγ antagonist GW9662. Results from the present study indicated that pioglitazone may improve insulin sensitivity and ameliorate Aβ42 accumulation in rats with diet‑induced IR by regulating AKT/GSK3β activation, suggesting that pioglitazone may be a promising drug for AD treatment.
吡格列酮可能作为阿尔茨海默病（AD）患者的一种替代治疗方法具有潜在益处，尤其是在同时患有糖尿病的个体中；然而，其作用机制仍不清楚。本研究旨在探讨吡格列酮对饮食诱导胰岛素抵抗（IR）大鼠淀粉样β蛋白42亚型（Aβ42）沉积的影响。在有或没有吡格列酮的情况下建立饮食诱导IR模型大鼠。测量血浆葡萄糖和胰岛素水平以及脑脊液胰岛素水平；此外，收集海马组织进行Aβ42表达的免疫组织化学分析。分别通过逆转录定量聚合酶链反应和蛋白质印迹法分析胰岛素降解酶（IDE）和过氧化物酶体增殖物激活受体γ（PPARγ）mRNA和蛋白表达水平。此外，通过蛋白质印迹法检测磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（AKT）信号诱导的糖原合酶激酶3β（GSK3β）的激活。本研究结果表明，吡格列酮可能增强饮食诱导IR模型大鼠的外周和脑胰岛素敏感性。吡格列酮治疗通过增加IDE和PPARγ表达改善海马中的Aβ42沉积。值得注意的是，PI3K/AKT/GSK3β途径的激活也被证明在吡格列酮诱导的Aβ42降解中起作用，这被PPARγ拮抗剂GW9662所消除。本研究结果表明，吡格列酮可能通过调节AKT/GSK3β激活来改善饮食诱导IR大鼠的胰岛素敏感性并减轻Aβ42积累，提示吡格列酮可能是一种有前途的AD治疗药物。
