Zhang Yonglan, Xia Zhining, Liu Jianhui, Yin Fei
College of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, P.R. China.
CNS Neurol Disord Drug Targets. 2015;14(3):370-7. doi: 10.2174/1871527314666141229110156.
An increasing number of studies have demonstrated that insulin-degrading enzyme (IDE) plays an essential role in both the degradation and its activity of β-amyloid (Aβ). Therefore, the regulation of IDE expression and/or modification of IDE-dependent actions are two emerging strategies for the treatment of Alzheimer's disease (AD). We previously observed that geniposide, a novel agonist of glucagon-like peptide 1 receptor (GLP-1R), could attenuate Aβ-induced neurotoxicity by regulating the expression of IDE in primary cortical neurons. However, the signal transduction mechanisms underlying this effect were not elucidated. The present study, therefore examined and explored the cell signaling transduction and molecular mechanisms by which geniposide induces the expression of IDE in primary cortical neurons. The current study revealed that LY294002 (an inhibitor for phosphatidyl inositol 3-kinase, PI3K), PP1 (inhibitor for c-Src), GW9662 (antagonist for peroxisome proliferator-activated receptor γ, PPARγ), H89 (an inhibitor for protein kinase A, PKA) and AG1478 (an antagonist for epidermal growth factor receptor, EGFR) prohibited the up-regulation of IDE induced by geniposide in primary cortical neurons. Further, geniposide also enhanced the phosphorylation of PPARγ and accelerated the release of phosphorylated FoxO1 (forkhead box O1) from nuclear fraction to the cytosol. Moreover, geniposide directly activated the activity of IDE promoter in PC12 cells, which confirmed the presence of the GLP-1 receptor. Taken together, our findings reveal for the first time the cell signaling transduction pathway of geniposide regulating the expression of IDE in neurons.
越来越多的研究表明，胰岛素降解酶（IDE）在β-淀粉样蛋白（Aβ）的降解及其活性方面均发挥着重要作用。因此，调节IDE表达和/或修饰IDE依赖性作用是治疗阿尔茨海默病（AD）的两种新兴策略。我们之前观察到，新型胰高血糖素样肽1受体（GLP-1R）激动剂京尼平苷可通过调节原代皮层神经元中IDE的表达来减轻Aβ诱导的神经毒性。然而，这种作用背后的信号转导机制尚未阐明。因此，本研究检测并探索了京尼平苷诱导原代皮层神经元中IDE表达的细胞信号转导和分子机制。当前研究表明，LY294002（磷脂酰肌醇3激酶，PI3K的抑制剂）、PP1（c-Src抑制剂）、GW9662（过氧化物酶体增殖物激活受体γ，PPARγ拮抗剂）、H89（蛋白激酶A，PKA抑制剂）和AG1478（表皮生长因子受体，EGFR拮抗剂）可抑制京尼平苷诱导的原代皮层神经元中IDE的上调。此外，京尼平苷还增强了PPARγ的磷酸化，并加速了磷酸化的叉头框蛋白O1（FoxO1）从核组分释放到细胞质中。此外，京尼平苷直接激活了PC12细胞中IDE启动子的活性，这证实了GLP-1受体的存在。综上所述，我们的研究结果首次揭示了京尼平苷调节神经元中IDE表达的细胞信号转导途径。
