In the previous reports, we showed that caspase-4, which has high homology to caspase-12, plays an important role in the neural cell death via the endoplasmic reticulum (ER) stress. In addition, we elucidated the involvement of the familial Alzheimer's disease (AD)-linked presenilin-1 (PS1) mutation and beta-amyloid induced-apoptotic signaling in human neural cells in the activation (cleavage) of caspase-4. These results suggest the involvement of caspase-4 in the cell death observed in AD. To elucidate the mechanism of the cleavage of caspase-4 under ER stress, we used EGTA, a Ca(2+) chelator, because the cleavage caspase-12 has reported to be regulated by the calpain. As the results, EGTA inhibited the cleavage of caspase-4 in a concentration-dependent manner. In addition, inhibitors of calpain, which are activated by the Ca(2+), also inhibited the cleavage of caspase-4. Furthermore, EGTA and caplain inhibitors rescued the neural cell death under the ER stress. These results suggest that the disturbance of Ca(2+) homeostasis induced by ER stress should cause the activation of caspase-4 resulting in the neural cell death.