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Title: Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice
Authors: Dominguez, Diana Ines
Tournoy, Jos
Hartmann, Dieter
Huth, Tobias
Cryns, Kim
Deforce, Siska
Serneels, Lutgarde
Camacho, Ira Espuny
Marjaux, Els
Craessaerts, Kathleen
Roebroek, Anton
Schwake, Michael
D'Hooge, Rudi
Bach, Patricia
Kalinke, Ulrich
Moechars, Dieder
Alzheimer, Christian
Reiss, Karina
Saftig, Paul
De Strooper, Bart # ×
Issue Date: Aug-2005
Publisher: American Society for Biochemistry and Molecular Biology
Series Title: Journal of Biological Chemistry vol:280 issue:35 pages:30797-30806
Abstract: 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.
URI: 
ISSN: 0021-9258
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
Laboratory for Biological Psychology
Laboratory for the Research of Neurodegenerative Diseases
Gerontology and Geriatrics
× corresponding author
# (joint) last author

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