The study investigates the role of caspase-4 in endoplasmic reticulum (ER) stress-induced apoptosis and amyloid-β (Aβ)-induced cell death. Caspase-4, a member of the caspase-1 subfamily, is localized to the ER membrane and is specifically cleaved by ER stress-inducing reagents but not by other apoptotic reagents. Overexpression of Bcl-2, which prevents signal transduction on mitochondria, does not affect caspase-4 cleavage, suggesting that caspase-4 is primarily activated in ER stress-induced apoptosis. Reduction of caspase-4 expression by small interfering RNA (siRNA) decreases ER stress-induced apoptosis in some cell lines but not in others. Caspase-4 is also cleaved by Aβ treatment, and Aβ-induced apoptosis is reduced by siRNA to caspase-4. These findings suggest that caspase-4 functions as an ER stress-specific caspase in humans and may be involved in the pathogenesis of Alzheimer's disease.The study investigates the role of caspase-4 in endoplasmic reticulum (ER) stress-induced apoptosis and amyloid-β (Aβ)-induced cell death. Caspase-4, a member of the caspase-1 subfamily, is localized to the ER membrane and is specifically cleaved by ER stress-inducing reagents but not by other apoptotic reagents. Overexpression of Bcl-2, which prevents signal transduction on mitochondria, does not affect caspase-4 cleavage, suggesting that caspase-4 is primarily activated in ER stress-induced apoptosis. Reduction of caspase-4 expression by small interfering RNA (siRNA) decreases ER stress-induced apoptosis in some cell lines but not in others. Caspase-4 is also cleaved by Aβ treatment, and Aβ-induced apoptosis is reduced by siRNA to caspase-4. These findings suggest that caspase-4 functions as an ER stress-specific caspase in humans and may be involved in the pathogenesis of Alzheimer's disease.