Focal Adhesion Kinase Activates NF-κB via the ERK1/2 and p38MAPK Pathways in Amyloid-β25-35-Induced Apoptosis in PC12 Cells

Increasing evidence supports that amyloid plaques, comprised of amyloid-beta (A beta), are a key feature of Alzheimer's disease (AD). But the mechanism of A beta in AD is not yet fully understood. Previous studies have demonstrated that in A beta-induced apoptosis of nerve cells, differentiated rat pheochromocytoma (PC12) cells, and microglia, nucleus factor kappa B (NF-kappa B) is activated. Meanwhile, focal adhesion kinase (FAK) is also activated. However, the relationship between NF-kappa B and FAK remains unclear. Using differentiated PC12 cells, we investigated this relationship in A beta(25-35)-induced apoptosis. The results showed that FAK phosphorylation increased at 6-9 hours after A beta treatment, slightly shorter than the activation of NF-kappa B (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-kappa B were all suppressed. When ERK1/2 and p38MAPK expressions were inhibited by their siRNAs respectively, NF-kappa B activity was also suppressed. But FAK phosphorylation was not affected. When NF-kappa B 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-kappa B, and meanwhile both of ERK1/2 and p38MAPK are upstream of NF-kappa B. Co-immunoprecipitation results demonstrated that it is ERK1/2, but not p38MAPK, which directly interacts with I kappa B kinase. Taken together, our results suggest that FAK activates NF-kappa B via ERK1/2 and p38MAPK pathways in A beta(25-35)-induced apoptosis of differentiated PC12 cells.