Early activation of caspase-3 by beta-amyloid peptides (25-35, 1-42) stimulates the activation of double-stranded RNA-regulated protein kinase and cleavage of eukaryotic initiation factor 2 alpha

Beta-amyloid (Aβ) peptide has been proposed to play important roles in the pathogenesis of Alzheimer’s disease. We have shown that Aβ peptides induce activation of double-stranded RNA-regulated protein kinase (PKR) and phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) in cultured neuronal cells during apoptosis. PKR mediates apoptosis by phosphorylating eIF2α, and in turn terminating global protein synthesis. In the present study, we further investigate the role of PKR and eIF2α in Aβ peptide-induced apoptosis. Western-blot results showed that eIF2α was cleaved by activated caspase-3 induced by Aβ peptides in rat primary cortical neurons. This result was confirmed by using a caspase-3 inhibitor, DEVD-CHO, which was shown to block Aβ peptides-induced cleavage of eIF2α. We also found that activation of PKR by Aβ peptides was caspase-3 dependent. Western-blot analysis revealed that PKR could not be activated by Aβ peptides if the activation of caspase-3 was blocked by its inhibitor (DEVD-CHO). Consequently, phosphorylation of eIF2α by PKR was also blocked by the caspase-3 inhibitor. These results lead us to conclude that PKR is a downstream pathway of caspase-3 and its activation is caspase-3 dependent in Aβ peptide-induced neuronal apoptosis. Physiological effects of cleaved eIF2α and caspase-3 dependent activation of PKR in the Aβ peptide-triggered apoptotic pathway will be further studied