{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:06:32Z","timestamp":1791266792891,"version":"4.1.0"},"reference-count":28,"publisher":"National Academy of Sciences","issue":"5","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2005,2]]},"abstract":"<jats:p>\n                    \u03b3-Secretase is the protease responsible for amyloid \u03b2 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\n                    <jats:italic>Aph1B<\/jats:italic>\n                    in rodents has given rise to a third gene,\n                    <jats:italic>Aph1C<\/jats:italic>\n                    . Different mixes of \u03b3-secretase subunits assemble in at least four human and six rodent complexes but it is not known whether they have different activities\n                    <jats:italic>in vivo<\/jats:italic>\n                    . We report here the inactivation of the three\n                    <jats:italic>Aph1<\/jats:italic>\n                    genes in mice.\n                    <jats:italic>Aph1A<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    embryos show a lethal phenotype characterized by angiogenesis defects in the yolk sac, neuronal tube malformations, and mild somitogenesis defects.\n                    <jats:italic>Aph1B<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    or\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    or the combined\n                    <jats:italic>Aph1BC<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice (which can be considered as a model for total\n                    <jats:italic>Aph1B<\/jats:italic>\n                    loss in human) survive into adulthood. However,\n                    <jats:italic>Aph1BC<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    deficiency causes a mild but significant reduction in amyloid \u03b2 percursor protein processing in selective regions of the adult brain. We conclude that the biochemical and physiological repercussions of genetically reducing \u03b3-secretase activity via the different\n                    <jats:italic>Aph1<\/jats:italic>\n                    components are quite divergent and tissue specific. Our work provides\n                    <jats:italic>in vivo<\/jats:italic>\n                    evidence for the concept that different \u03b3-secretase complexes may exert different biological functions. In the context of Alzheimer's disease therapy, this implies the theoretical possibility that targeting specific \u03b3-secretase subunit combinations could yield less toxic drugs than the currently available general inhibitors of \u03b3-secretase activity.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0408901102","type":"journal-article","created":{"date-parts":[[2005,1,21]],"date-time":"2005-01-21T20:41:41Z","timestamp":1106340101000},"page":"1719-1724","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":155,"title":["Differential contribution of the three Aph1 genes to \u03b3-secretase activity\n                    <i>in vivo<\/i>"],"prefix":"10.1073","volume":"102","author":[{"given":"Lutgarde","family":"Serneels","sequence":"first","affiliation":[{"name":"Neuronal Cell Biology and Membrane Transport Laboratories, and Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium; and Department of Molecular Animal Physiology, Radboud University Nijmegen, 6500 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Dejaegere","sequence":"additional","affiliation":[{"name":"Neuronal Cell Biology and Membrane Transport Laboratories, and Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium; and Department of Molecular Animal Physiology, Radboud University Nijmegen, 6500 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katleen","family":"Craessaerts","sequence":"additional","affiliation":[{"name":"Neuronal Cell Biology and Membrane Transport Laboratories, and Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium; and Department of Molecular Animal Physiology, Radboud University Nijmegen, 6500 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrien","family":"Horr\u00e9","sequence":"additional","affiliation":[{"name":"Neuronal Cell Biology and Membrane Transport Laboratories, and Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium; and Department of Molecular Animal Physiology, Radboud University Nijmegen, 6500 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Jorissen","sequence":"additional","affiliation":[{"name":"Neuronal Cell Biology and Membrane Transport Laboratories, and Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium; and Department of Molecular Animal Physiology, Radboud University Nijmegen, 6500 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Tousseyn","sequence":"additional","affiliation":[{"name":"Neuronal Cell Biology and Membrane Transport Laboratories, and Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium; and Department of Molecular Animal Physiology, Radboud University Nijmegen, 6500 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"H\u00e9bert","sequence":"additional","affiliation":[{"name":"Neuronal Cell Biology and Membrane Transport Laboratories, and Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium; and Department of Molecular Animal Physiology, Radboud University Nijmegen, 6500 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Coolen","sequence":"additional","affiliation":[{"name":"Neuronal Cell Biology and Membrane Transport Laboratories, and Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium; and Department of Molecular Animal Physiology, Radboud University Nijmegen, 6500 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard","family":"Martens","sequence":"additional","affiliation":[{"name":"Neuronal Cell Biology and Membrane Transport Laboratories, and Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium; and Department of Molecular Animal Physiology, Radboud University Nijmegen, 6500 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Zwijsen","sequence":"additional","affiliation":[{"name":"Neuronal Cell Biology and Membrane Transport Laboratories, and Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium; and Department of Molecular Animal Physiology, Radboud University Nijmegen, 6500 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim","family":"Annaert","sequence":"additional","affiliation":[{"name":"Neuronal Cell Biology and Membrane Transport Laboratories, and Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium; and Department of Molecular Animal Physiology, Radboud University Nijmegen, 6500 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Neuronal Cell Biology and Membrane Transport Laboratories, and Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium; and Department of Molecular Animal Physiology, Radboud University Nijmegen, 6500 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"De Strooper","sequence":"additional","affiliation":[{"name":"Neuronal Cell Biology and Membrane Transport Laboratories, and Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Katholieke Universiteit Leuven, Leuven B-3000, Belgium; 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