Identification of distinct gamma-secretase complexes with different APH-1 variants.
The gamma-secretase complex catalyzes the final intramembraneous cleavage of the beta-amyloid precursor protein, liberating the neurotoxic amyloid beta-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 gamma-secretase complexes, exist. Likewise, two APH-1 homologues, APH-1a and APH-1b, have been identified. Furthermore, two APH-1a splice forms, APH-1aS 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 gamma-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 gamma-secretase activity, whereas deficiency of APH-1b was not. Thus, APH-1b gamma-secretase complexes may fulfill redundant functions. Taken together, our results suggest that, dependent on the tissue expression of the individual subunits, six distinct gamma-secretase complexes composed of the known subunits can exist in human cells.
Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Schillerstrasse 44, Ludwig-Maximilians-University, 80336 Munich, Germany.
Keiro
K
Shirotani
Dieter
D
Edbauer
Stefan
S
Prokop
Christian
C
Haass
Harald
H
Steiner
D017398:Alternative Splicing; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D002460:Cell Line; D010450:Endopeptidases / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism; D008565:Membrane Proteins / Q000032:analysis / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D010447:Peptide Hydrolases; D053764:Presenilin-1; D053766:Presenilin-2; D011485:Protein Binding; D020033:Protein Isoforms / Q000032:analysis / Q000378:metabolism; D021122:Protein Subunits / Q000032:analysis; D014162:Transfection
D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; C469349:PSENEN protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D020033:Protein Isoforms; D021122:Protein Subunits; C413604:nicastrin protein; C475154:APH1A protein, human; C475155:APH1B protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human