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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.

Pubmed ID: 10638761


  • Nakagawa T
  • Zhu H
  • Morishima N
  • Li E
  • Xu J
  • Yankner BA
  • Yuan J



Publication Data

January 6, 2000

Associated Grants


Mesh Terms

  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Animals
  • Apoptosis
  • Caspase 12
  • Caspases
  • Cells, Cultured
  • Cerebral Cortex
  • Cytotoxins
  • Endoplasmic Reticulum
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Kidney
  • Mice
  • Mice, Knockout
  • Mutagenesis
  • Neurons
  • PC12 Cells
  • Rats
  • Thymus Gland
  • Tunicamycin