Endogenous β-amyloid production in presenilin-deficient embryonic mouse fibroblasts

Genetic and biochemical evidence have led to the suggestion that presenilins could be the long-searched-for gamma -secretase, the proteolytic activity that generates the carboxy terminus of amyloid beta -peptides. This activity is also thought to be responsible for the release of the Notch intracellular 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 the endogenous production of A beta 40 and A beta 42 was not altered by presenilin deficiency. By contrast, inactivating presenilin genes fully abolished NICD production. These data indicate that A beta and NICD production are distinct catabolic events. Also, even though NICD formation is indeed presenilin dependent, endogenous secreted and intracellular beta -amyloid peptides are still generated in absence of presenilins, indicating that there is a gamma -secretase activity distinct from presenilins, at least in murine fibroblasts.