MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.
J Alzheimers Dis. 2012;32(1):77-94. doi: 10.3233/JAD-2012-120526.
Increasing evidence supports that amyloid plaques, comprised of amyloid-β (Aβ), are a key feature of Alzheimer's disease (AD). But the mechanism of Aβ in AD is not yet fully understood. Previous studies have demonstrated that in Aβ-induced apoptosis of nerve cells, differentiated rat pheochromocytoma (PC12) cells, and microglia, nucleus factor kappa B (NF-κB) is activated. Meanwhile, focal adhesion kinase (FAK) is also activated. However, the relationship between NF-κB and FAK remains unclear. Using differentiated PC12 cells, we investigated this relationship in Aβ(25-35)-induced apoptosis. The results showed that FAK phosphorylation increased at 6-9 hours after Aβ treatment, slightly shorter than the activation of NF-κB (6-12 hours). In this process, both extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation levels were increased. After FAK expression was inhibited by its siRNA, the activities of ERK1/2, p38MAPK, and NF-κB were all suppressed. When ERK1/2 and p38MAPK expressions were inhibited by their siRNAs respectively, NF-κB activity was also suppressed. But FAK phosphorylation was not affected. When NF-κB expression was inhibited, all of the phosphorylation levels of FAK, ERK1/2, and p38MAPK were not affected. These phenomena indicated that FAK is upstream of ERK1/2, p38MAPK, and NF-κB, and meanwhile both of ERK1/2 and p38MAPK are upstream of NF-κB. Co-immunoprecipitation results demonstrated that it is ERK1/2, but not p38MAPK, which directly interacts with IκB kinase. Taken together, our results suggest that FAK activates NF-κB via ERK1/2 and p38MAPK pathways in Aβ(25-35)-induced apoptosis of differentiated PC12 cells.
越来越多的证据表明，由淀粉样β（Aβ）组成的淀粉样斑块是阿尔茨海默病（AD）的一个关键特征。但是，Aβ在 AD 中的作用机制尚未完全阐明。先前的研究表明，在 Aβ诱导的神经细胞、分化的大鼠嗜铬细胞瘤（PC12）细胞和小胶质细胞凋亡中，核因子 kappa B（NF-κB）被激活。同时，粘着斑激酶（FAK）也被激活。然而，NF-κB 和 FAK 之间的关系尚不清楚。本研究使用分化的 PC12 细胞，研究了 Aβ（25-35）诱导的凋亡中两者之间的关系。结果表明，Aβ 处理 6-9 小时后 FAK 磷酸化增加，稍早于 NF-κB 的激活（6-12 小时）。在此过程中，细胞外信号调节激酶 1/2（ERK1/2）和 p38 丝裂原激活蛋白激酶（p38MAPK）的磷酸化水平均增加。用其 siRNA 抑制 FAK 表达后，ERK1/2、p38MAPK 和 NF-κB 的活性均受到抑制。当分别用其 siRNA 抑制 ERK1/2 和 p38MAPK 的表达时，NF-κB 的活性也受到抑制。但 FAK 的磷酸化不受影响。当抑制 NF-κB 的表达时，FAK、ERK1/2 和 p38MAPK 的磷酸化水平均不受影响。这些现象表明，FAK 是 ERK1/2、p38MAPK 和 NF-κB 的上游，同时 ERK1/2 和 p38MAPK 都是 NF-κB 的上游。免疫共沉淀结果表明，直接与 IκB 激酶相互作用的是 ERK1/2，而不是 p38MAPK。综上所述，本研究结果表明，在 Aβ（25-35）诱导的分化 PC12 细胞凋亡中，FAK 通过 ERK1/2 和 p38MAPK 途径激活 NF-κB。
