Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. 
Apoptosis, or cellular suicide, is important for normal development and tissue homeostasis, but too much or too little apoptosis can also cause disease.  The family of cysteine proteases, the so- called caspases, are critical mediators of programmed cell death, and thus far 14 family members have been identified.  Some of these, such as caspase-8, mediate signal transduction downstream of death receptors located on the plasma membrane.  Others, such as caspase-9, mediate apoptotic signals after mitochondrial damage.  Stress in the endoplasmic reticulum (ER) can also result in apoptosis.  Here we show that caspase-12 is localized to the ER and activated by ER stress, including disruption of ER calcium homeostasis and accumulation of excess proteins in ER, but not by membrane- or mitochondrial-targeted apoptotic signals.  Mice that are deficient in caspase-12 are resistant to ER stress-induced apoptosis, but their cells undergo apoptosis in response to other death stimuli.  Furthermore, we show that caspase-12-deficient cortical neurons are defective in apoptosis induced by amyloid-beta protein but not by staurosporine or trophic factor deprivation.  Thus, caspase-12 mediates an ER-specific apoptosis pathway and may contribute to amyloid-beta neurotoxicity.