Identification of caspases that cleave presenilin-1 and presenilin-2 - Five presenilin-1 (PS1) mutations do not alter the sensitivity of PS1 to caspases

Mutations in the presenilin (PS) genes PS1 and PS2 are involved in Alzheime r's disease (AD), Recently, apoptosis-associated cleavage of PS proteins wa s identified. Here we demonstrate that PS1 as well as PS2 are substrates fo r different members of the caspase protein family. Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing cas pase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser exte nt after residues AQRD(341). A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341 Importantly, these two cleavage sites were al so recognized by caspases in the C-terminal PS1 fragment produced by consti tutive proteolysis. In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329 Caspase-8 and -3 exhibited the highest proteolytic activity on both PS1 and PS2, PSI and PS2 were not hydrolyzed by caspase-2 and PS2 also not by caspase-11, None of f ive missense mutations affected the sensitivity of PS1 to caspase-mediated cleavage. This suggests that AD pathogenesis associated with PS1 missense m utations cannot be explained by a change in caspase-dependent processing. ( C) 1999 Federation of European Biochemical Societies.