[en] Beta-secretase (BACE1) is the rate-limiting protease for the generation of the amyloid beta-peptide (Abeta) in Alzheimer disease. Mice in which the bace1 gene is inactivated are reported to be healthy. However, the presence of a homologous gene encoding BACE2 raises the possibility of compensatory mechanisms. Therefore, we have generated bace1, bace2, and double knockout mice. We report here that BACE1 mice display a complex phenotype. A variable but significant number of BACE1 offspring died in the first weeks after birth. The surviving mice remained smaller than their littermate controls and presented a hyperactive behavior. Electrophysiologically, subtle alterations in the steady-state inactivation of voltage-gated sodium channels in BACE1-deficient neurons were observed. In contrast, bace2 knockout mice displayed an overall healthy phenotype. However, a combined deficiency of BACE2 and BACE1 enhanced the bace1-/- lethality phenotype. At the biochemical level, we have confirmed that BACE1 deficiency results in an almost complete block of Abeta generation in neurons, but not in glia. As glia are 10 times more abundant in brain compared with neurons, our data indicate that BACE2 could indeed contribute to Abeta generation in the brains of Alzheimer disease and, in particular, Down syndrome patients. In conclusion, our data challenge the general idea of BACE1 as a safe drug target and call for some caution when claiming that no major side effects should be expected from blocking BACE1 activity.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Dominguez, D; VIB, KU Leuven, 3000 Leuven, Belgium > Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology
Tournoy, J; VIB, KU Leuven, 3000 Leuven, Belgium > Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology
Hartmann, D; VIB, KU Leuven, 3000 Leuven, Belgium > Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology
Huth, T; University Kiel, D-24098 Kiel, Germany > Department of Physiology
Cryns, K; Johnson & Johnson, B-2340 Beerse, Belgium, > Pharmaceutical Research and Development
Deforce, S; VIB, KU Leuven, 3000 Leuven, Belgium > Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology
Serneels, L; VIB, KU Leuven, 3000 Leuven, Belgium > Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology
Espuny Camacho, Ira Mercedes ; VIB, KU Leuven, 3000 Leuven, Belgium > Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology
Marjaux, E; VIB, KU Leuven, 3000 Leuven, Belgium > Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology
Craessaerts, K; VIB, KU Leuven, 3000 Leuven, Belgium > Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology
Roebroek, AJ; KU Leuven, 3000 Leuven, Belgium > Center for Human Genetics
Schawke, M; University Kiel, Eduard-Buchner-Haus, D-24118 Kiel, Germany > Department of Biochemistry
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