Differential contribution of the three Aph1 genes to gamma-secretase activity in vivo.
Gamma-secretase is the protease responsible for amyloid beta peptide release and is needed for Notch, N-Cadherin, and possibly other signaling pathways. The protease complex consists of at least four subunits, i.e., Presenilin, Aph1, Pen2, and Nicastrin. Two different genes encode Aph1A and Aph1B in man. A duplication of Aph1B in rodents has given rise to a third gene, Aph1C. Different mixes of gamma-secretase subunits assemble in at least four human and six rodent complexes but it is not known whether they have different activities in vivo. We report here the inactivation of the three Aph1 genes in mice. Aph1A-/- embryos show a lethal phenotype characterized by angiogenesis defects in the yolk sac, neuronal tube malformations, and mild somitogenesis defects. Aph1B-/- or C-/- or the combined Aph1BC-/- mice (which can be considered as a model for total Aph1B loss in human) survive into adulthood. However, Aph1BC-/- deficiency causes a mild but significant reduction in amyloid beta percursor protein processing in selective regions of the adult brain. We conclude that the biochemical and physiological repercussions of genetically reducing gamma-secretase activity via the different Aph1 components are quite divergent and tissue specific. Our work provides in vivo evidence for the concept that different gamma-secretase complexes may exert different biological functions. In the context of Alzheimer's disease therapy, this implies the theoretical possibility that targeting specific gamma-secretase subunit combinations could yield less toxic drugs than the currently available general inhibitors of gamma-secretase activity.
Serneels
Lutgarde
L
Neuronal Cell Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium.
Dejaegere
Tim
T
Craessaerts
Katleen
K
Horré
Katrien
K
Jorissen
Ellen
E
Tousseyn
Thomas
T
Hébert
Sébastien
S
Coolen
Marcel
M
Martens
Gerard
G
Zwijsen
An
A
Annaert
Wim
W
Hartmann
Dieter
D
De Strooper
Bart
B
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001808:Blood Vessels / Q000196:embryology / Q000254:growth & development; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D017353:Gene Deletion; D006580:Genetic Carrier Screening; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000235:genetics; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics*
D008565:Membrane Proteins; D020033:Protein Isoforms; D021122:Protein Subunits; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; C498196:Aph1C protein, mouse; C498194:Aph1a protein, mouse; C498195:Aph1b protein, mouse