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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.

Pubmed ID: 15665098

Authors

  • Serneels L
  • Dejaegere T
  • Craessaerts K
  • Horré K
  • Jorissen E
  • Tousseyn T
  • Hébert S
  • Coolen M
  • Martens G
  • Zwijsen A
  • Annaert W
  • Hartmann D
  • De Strooper B

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 1, 2005

Associated Grants

None

Mesh Terms

  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases
  • Blood Vessels
  • Endopeptidases
  • Gene Deletion
  • Heterozygote Detection
  • Mice
  • Mice, Knockout
  • Protein Isoforms
  • Protein Subunits