A caspase protease in the endoplasmic reticulum (ER) may have a hand in cell death in Alzheimer's, according to a report in the January 6 issue of Nature. (Apologies for the delay in reporting this story!) The caspases, a family of cysteine proteases (14 identified to date), appear to play critical roles in various apoptotic mechanisms. Caspases have been found at work following activation of death receptors at the cell surface and following mitochondrial damage. Junying Yuan and her team at Harvard have now found a role for another member of the family, caspase-12, a protease that causes apoptosis when overexpressed.
They were able to show that caspase-12 can be localized to the ER, in contrast to most other caspases, which are found in the cytosol. The researchers also showed that a process called ER stress (a buildup of proteins in the ER that leads to apoptosis) upregulates the cleavage of caspase-12 from a precursor, suggesting that the protease facilitates the cell death that results from ER stress. (By contrast, apoptosis resulting from cell membrane or mitochondrial pathways did not upregulate caspase-12.) Yuan's group tested this hypothesis in vivo, determining that mice deficient in caspase-12 are resistant to ER stress apoptosis, but not to apoptosis from other causes.
The researchers then examined the ER-stress apoptosis/caspase-12 link from a perspective of specific interest to Alzheimer's research. This line of investigation was based on the observation that the ER membrane has a receptor specific for amyloid-β (Aβ), which can induce apoptosis. They found that cortical neurons from the caspase-12 deficient mice were resistant to Aβ-induced apoptosis in vitro, though not to apoptosis by other stimuli.
Writing a News and Views letter in the same issue, Huseyin Mehmet of the Imperial College of Science, Technology and Medicine in London notes that another family member-caspase-3-has been shown to cleave the Aβ precursor protein (APP) and discusses a mode of cell death in Alzheimer's that puts APP and the much-discussed presenilins on the sidelines. He suggests that caspase-3 cleaves APP and the resulting Aβ activates caspase-12-dependent apoptosis. For both Mehmet and Yuan and colleagues, the obvious implications are that caspase-12 could become a target for Alzheimer's treatment.—Hakon Heimer
No Available References
- Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 2000 Jan 6;403(6765):98-103. PubMed.