ALZHEIMERS-DISEASE ASSOCIATED PRESENILIN-1 HOLOPROTEIN AND ITS 18-20 KDA C-TERMINAL FRAGMENT ARE DEATH SUBSTRATES FOR PROTEASES OF THE CASPASE FAMILY

Mutations in the presenilin (PS) genes are linked to early onset famil ial Alzheimer's disease (FAD). PS-1 proteins are proteolytically proce ssed by an unknown protease leading to the formation of two stable fra gments of similar to 30 and similar to 20 kDa [Thinakaran, G., et al. (1996) Neuron 17, 181-190]. In addition to the conventional fragments, alternative cleavage products were observed as well. Here we characte rize an alternative proteolytic pathway of PS-1 which involves proteas es of the caspase superfamily. Caspase mediated cleavage occurs betwee n aspartate 345 and serine 346 C-terminal to the conventional cleavage determined previously [Podlisny, M., et al., (1997) Neurobiol. Dis, 3 , 325-337]. Full-length PS-1 can serve as a substrate for caspase-like proteases, as demonstrated by the generation of the alternative C-ter minal fragment in cells expressing PS-1 containing the Delta exon 10 d eletion which is known to accumulate as a full-length molecule [Thinak aran, G., et al. (1996)]. By inhibition of de novo protein synthesis i n untransfected cells we demonstrate that the conventional C-terminal fragment of PS-1 is a substrate for caspase-like proteases as well. Th erefore full-length and the conventional C-terminal fragment of PS-1 c an serve as potential death substrates. Due to the fact that very litt le full-length PS-1 is expressed in vivo, the much more abundant C-ter minal fragment and not the full-length precursor is the major in vivo substrate for the alternative cleavage of PS-1 by proteases of the cas pase superfamily.