Detection of the presenilin 1 COOH-terminal fragment in the extracellular compartment: A release enhanced by apoptosis

Mutations in gene encoding presenilin 1 (PSI) are responsible for the major ity of familial Alzheimer's disease (FAD) cases. We studied PS1 localizatio n in HEK293 cells and in primary neurons obtained from rat cortex and hippo campus. We first demonstrated that PS1-CTF, but neither PS1-FL nor PS1-NTF, is released into the medium as a soluble and membrane-associated form. Aft er induction of apoptosis with staurosporine (Sts), we observed a dramatic increase in the level of PS1-CTF in the medium, both in HEK293 and in prima ry neurons. Immunocytochemical analysis suggested that the release of PS1-C TF might occur via membrane shedding. A beta (1-42) treatment reduced PS1-C TF extracellular levels. This decrease was strongly associated to an impair ed secretion of sAPP fragments, thus suggesting a role of PS1-CTF in the co ntrol of trafficking and generation of APP fragments. (C) 2001 Academic Pre ss.