This item still needs to be validated !
Title: Differential contribution of the three Aph1 genes to gamma-secretase activity in vivo
Authors: Serneels, Lutgarde
Dejaegere, Tim
Craessaerts, Kathleen
Horré, Katrien
Jorissen, Ellen
Tousseyn, Thomas
Hébert, Sébastien
Coolen, Marcel
Martens, Gerard
Zwijsen, An
Annaert, Wim
Hartmann, Dieter
De Strooper, Bart # ×
Issue Date: Feb-2005
Publisher: National Academy of Sciences
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:102 issue:5 pages:1719-24
Abstract: 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.
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
Molecular Biology (Celgen) (-)
Laboratory for the Research of Neurodegenerative Diseases
Translational Cell & Tissue Research
× corresponding author
# (joint) last author

Files in This Item:
File Description Status SizeFormat
1719.full.pdfOA article Published 827KbAdobe PDFView/Open Request a copy

These files are only available to some KU Leuven Association staff members


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science