Presenilin 1 (PS1) and presenilin 2 (PS2) are homologous transmembrane proteins genetically associated with Alzheimer disease. As previously reported by our group for PS1, here we demonstrated that, in mouse primary neurons and microglial cells, PS2 C-terminal fragment (CTF) is released by shedding into the extracellular compartment as a soluble form and that this release is 4.07-fold increased during apoptosis. When compared with PS1, PS2 seems to be more susceptible to apoptosis since its secretion is increased 2.8-fold more than PS1. During apoptosis either proteins were colocalized especially within shedded vesicles. The present study suggest an active role for the presenilins CTF on putative target cells.