Identification of Distinct -Secretase Complexes with Different

The -secretase complex catalyzes the final intramembraneous cleavage of the -amyloid precursor protein, liberating the neurotoxic amyloid -peptide implicated in Alzheimer’s disease. Apart from the catalytic subunit presenilin (PS), three additional subunits, nicastrin, APH-1, and PEN-2, have been identified. In mammals, two PS homologues, PS1 and PS2, which are part of distinct -secretase complexes, exist. Likewise, two APH-1 homologues, APH-1a and APH-1b, have been identified. Furthermore, two APH-1a splice forms, APH1aS and APH-1aL, have been reported. Here we show that both APH-1a splice forms and APH-1b are expressed in peripheral and neuronal cells. APH-1aS, APH-1aL, and APH-1b form separate, proteolytically active -secretase complexes containing either one of the two PSs. Deficiency of APH-1a caused a decrease in nicastrin, PS, and PEN-2 levels and an increase in the levels of APH-1b, whereas deficiency of APH-1b did not affect the levels of APH-1a or the other complex components. Consistent with this finding, we found that deficiency of APH-1a was associated with reduced -secretase activity, whereas deficiency of APH-1b was not. Thus, APH-1b -secretase complexes may fulfill redundant functions. Taken together, our results suggest that, dependent on the tissue expression of the individual subunits, six distinct -secretase complexes composed of the known subunits can exist in human cells.