Three distinct signaling pathways lead to programmed cell death (apoptosis). The death receptor and mitochondrion pathways are the mains two pathways, in which the key apoptotic proteases caspase-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 located to the ER, but not to the cytoplasm or mitochondrion. Caspase-12 is activated by ER stress, including disruption of ER calcium hemeostasis, and mediates ER stress-induced apoptosis. Caspase-12 is localized to the ER with several proteins that are involved in Alzheimer’s disease including gamma-secretase presenilin and β-amyloid precursor protein (APP). Caspase-12 mediates cytotoxicity induced by amyloid-β. Caspase-12 is ubiquitously expressed in mouse tissues.