Nicastrin is a 75 kDa protein that was isolated at stoichiometric levels to PS1. Engineered amino acid substitutions of nicastrin at the DYIGS motif that is conserved between the nicastrin homologs, enhanced release of both Aβ40 and Aβ42. Deletion mutants of DYIGS paradoxically reduced Aβ production, a situation that has been described at certain positions in PS1. In C. elegans, reduced activity of the nicastrin homolog produced notch/glp-1 phenotypes, consistent with the concept that nicastin may facilitate Notch and APP proteolysis. From these intriguing first set of results, much work needs to be done.

Nevertheless, it certainly indicates that a functional complex consisting of presenilins and nicastrin work in coordination to facilitate Notch and APP signaling. It also indicates that simple reconstitution of presenilins and APP (or notch) is unlikely to demonstrate biological activity. For those who believe that presenilins are γ-secretases, this report is not against that notion. For those who feel that presenilins are not the actual γ-secretases, this report suggests that there is much more behind how presenilins work. Indeed, the full complex has yet to be fully eludicated and the actual protease activity remains to be discovered.-by Eddie Koo.