Three distinct signaling pathways lead to programmed cell death (apoptosis). The death receptor and mitochondrion pathways are the main, in which the key apoptotic proteases capase-8 and caspase-9, respectively, are involved. The endoplasmic reticulum (ER) stress is the third apoptotic pathway and caspase-12 is involved. Caspase-12 is localized to the ER but not to cytoplasm or mitochondrion. Caspase-12 is activated by ER stress, including disruption of ER calcium homeostasis, and mediates ER stress-induced apoptosis. Caspase-12 is co-localized to the ER with several proteins that are involved in Alzheimer's disease including gamma-secretase presenilin and beta-amyloid precursor protein (APP). Caspase-12 mediates cytotoxicity induced by amyloid-beta. Caspase-12 is ubiquitously expressed in mouse tissues.