Endogenous beta-amyloid production in presenilin-deficient embryonic mousefibroblasts

Genetic and biochemical evidence have led to the suggestion that presenilin s could be the long-searched-for gamma -secretase, the proteolytic activity that generates the carboxy terminus of amyloid beta -peptides. This activi ty is also thought to be responsible for the release of the Notch intracell ular domain (NICD) from Notch. Here, we report the production of endogenous secreted and intracellular 40- and 42-amino-acid A beta peptides in mouse fibroblasts deficient in presenilin 1, presenilin 2 or both. We show that t he endogenous production of A beta 40 and A beta 42 was not altered by pres enilin deficiency. By contrast, inactivating presenilin genes fully abolish ed NICD production. These data indicate that A beta and NICD production are distinct catabolic events. Also, even though NICD formation is indeed pres enilin dependent, endogenous secreted and intracellular beta -amyloid pepti des are still generated in absence of presenilins, indicating that there is a gamma -secretase activity distinct from presenilins, at least in murine fibroblasts.