You Fuling, Li Qiao, Jin Guifang, Zheng Yaojie, Chen Jingrong, Yang Hong
Basic Medical College, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China.
BMC Neurosci. 2017 Jan 12;18(1):12. doi: 10.1186/s12868-016-0329-9.
Deposition of aggregated amyloid beta (Aβ) protein is hallmark of Alzheimer's disease, leading to dysfunction and apoptosis of neurons. The isoflavone phytoestrogen compound genistein (Gen) exerts a significant protective effect against Aβ induced neurotoxicity and mitochondrial damage in rat pheochromocytoma (PC12) cells. However, the mechanisms underlying Gen's rescue remain elusive. Therefore we endeavored to research further the molecular mechanisms underlying Gen's inhibition of Aβ induced apoptosis of neurons.
We found that Gen dramatically suppressed the activation by Aβ of p-c-Jun N-terminal kinase (p-JNK), and also inhibited the JNK-dependent decreased of Bcl-w and increased of Bim. Furthermore, Gen significantly reduced the cytoplasmic concentrations of cytochrome c and Smac protein as well as caspase-3 activity. Additionally, pretreatment with JNK inhibitor SP600125 effectively suppressed Aβ induced PC12 cell cytotoxicity.
Taken together, the results suggested that Gen protects PC12 cells from Aβ induced neurotoxicity by interfering with p-JNK activation, thus attenuating the JNK-dependent apoptosis through the mitochondrial pathway. These findings constitute novel insights into the pathway for Aβ toxicity, and the neuroprotective action of Gen.
聚集的β淀粉样蛋白（Aβ）沉积是阿尔茨海默病的标志，会导致神经元功能障碍和凋亡。异黄酮类植物雌激素化合物染料木黄酮（Gen）对Aβ诱导的大鼠嗜铬细胞瘤（PC12）细胞神经毒性和线粒体损伤具有显著的保护作用。然而，Gen发挥保护作用的机制仍不清楚。因此，我们致力于进一步研究Gen抑制Aβ诱导的神经元凋亡的分子机制。
我们发现Gen显著抑制Aβ对磷酸化c-Jun氨基末端激酶（p-JNK）的激活，并且还抑制JNK依赖的Bcl-w减少和Bim增加。此外，Gen显著降低细胞色素c和Smac蛋白的细胞质浓度以及半胱天冬酶-3活性。另外，用JNK抑制剂SP600125预处理可有效抑制Aβ诱导的PC12细胞毒性。
综上所述，结果表明Gen通过干扰p-JNK激活来保护PC12细胞免受Aβ诱导的神经毒性，从而通过线粒体途径减弱JNK依赖的凋亡。这些发现为Aβ毒性途径以及Gen的神经保护作用提供了新的见解。
