Some of the attention focused on amyloid-β may have to be diverted to yet another peptide product of amyloid precursor protein (APP). Daniel Lu, Edward Koo and colleagues report in the April issue of Nature Medicine that the 31 amino-acid peptide from the C-terminal of APP could be involved in AD neuronal death, perhaps even in concert with Aβ. Their results indicate that both caspase-8 and caspase-9 cleave APP to form the C31 peptide, which is cytotoxic to cultured cells. They also determined that the previously demonstrated cytotoxicity of the C100 peptide is dependent on that final 31-amino-acid fragment. Finally, in AD brains, but not in control tissue, they found evidence of intracytoplasmic APP cleavage (presumed to be caspase-mediated) and activation of caspase-9.
They suggest that increased C31 production could have feedback amplification effects on caspase-8 production and thus on apoptotic mechanisms. This mechanism, the authors say, "does not exclude Aβ toxicity, and in fact complements proposed mechanisms that include Aβ toxicity. Indeed, C31 may function in concert with Aβ to produce the neuronal loss that characterizes AD."
"It may be very important if apoptosis via C31 is involved in AD pathogenesis," comments Hiroshi Mori of Osaka City University Medical School. If this is the case, he says, we will need to know "how and where does C31 peptide play a role in brains with AD?"—Hakon Heimer
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