Pathological activity of familial Alzheimer's disease-associated mutant presenilin can be executed by six different gamma-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 (Abeta) implicated in Alzheimer's disease (AD) pathogenesis. In human cells, six gamma-secretase complexes exist, which are composed of either presenilin (PS) 1 or 2, the catalytic subunit, nicastrin, PEN-2, and either APH-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 PS1 or PS2 support pathogenic Abeta(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.
Shirotani
Keiro
K
Munich Center for Integrated Protein Science and Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University, Schillerstr 44, Munich, Germany.
Tomioka
Masanori
M
Kremmer
Elisabeth
E
Haass
Christian
C
Steiner
Harald
H
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007668:Kidney / Q000166:cytology; D009097:Multienzyme Complexes / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D053766:Presenilin-2 / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009097:Multienzyme Complexes; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases