Pathological activity of familial Alzheimer's disease-associated mutant presenilin can be executed by six different γ-secretase complexes

gamma-Secretase is a protease complex, which catalyzes the final of two subsequent cleavages of the beta-amyloid precursor protein (APP) to release the amyloid-beta peptide (A beta) implicated in Alzheimer's disease (AD) pathogenesis. In human cells, six gamma-secretase complexes exist, which are composed of either presenilin (PS) I or 2, the catalytic subunit, nicastrin, PEN-2, and either APR-1a (as S or L splice variants) or its homolog APH-1b. It is not known whether and how different APH-1 species contribute to the pathogenic activity of,gamma-secretase complexes with familial AD (FAD) -associated mutant PS. Here we show that all known gamma-secretase complexes are active in APP processing and that all combinations of APH-1 variants with either FAD mutant PSI or PS2 support pathogenic A beta(42) production. Since our data suggest that pathogenic gamma-secretase activity cannot be attributed to a discrete gamma-secretase complex, we propose that all, gamma-secretase complexes have to be explored and evaluated for their potential as AD drug target. (c) 2007 Elsevier Inc. All rights reserved.