ALTERNATIVE CLEAVAGE OF ALZHEIMER-ASSOCIATED PRESENILINS DURING APOPTOSIS BY A CASPASE-3 FAMILY PROTEASE

Most cases of early-onset familiar Alzheimer's disease (FAD) are cause d by mutations in the genes encoding the presenilin 1 (PS1) and PS2 pr oteins, both of which undergo regulated endoproteolytic processing. Du ring apoptosis, PS1 and PS2 were shown to be cleaved at sites distal t o their normal cleavage sites by a caspase-3 family protease. In cells expressing PS2 containing the asparagine-141 FAD mutant, the ratio of alternative to normal PS2 cleavage fragments was increased relative t o wild-type PS2-expressing cells, suggesting a potential role for apop tosis-associated cleavage of presenilins in the pathogenesis of Alzhei mer's disease.