Presenilin 1 regulates pharmacologically distinct γ-secretase activities: Implications for the role of presenilin in γ-secretase cleavage

Presenilins (PSs) are polytopic membrane proteins that have been implicated as potential therapeutic targets in Alzheimer's disease because of their role in regulating the γ-secretase cleavage that generates the amyloid β protein (Aβ). It is not clear how PSs regulate γ-secretase cleavage, but there is evidence that PSs could be either essential cofactors in the γ-secretase cleavage, γ-secretase themselves, or regulators of intracellular trafficking that indirectly influence γ-secretase cleavage. Using presenilin 1 (PS1) mutants that inhibit Aβ production in conjunction with transmembrane domain mutants of the amyloid protein precursor that are cleaved by pharmacologically distinct γ-secretases, we show that PS1 regulates multiple pharmacologically distinct γ-secretase activities as well as inducible α-secretase activity. It is likely that PS1 acts indirectly to regulate these activities (as in a trafficking or chaperone role), because these data indicate that for PS1 to be γ-secretase it must either have multiple active sites or exist in a variety of catalytically active forms that are altered to an equivalent extent by the mutations we have studied.