Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice.
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.
Center for Human Genetics, Katholieke Universiteit Leuven and Flanders Interuniversity Institute for Biotechnology VIB4, Herestraat 49, 3000 Leuven, Belgium.
Diana
D
Dominguez
Jos
J
Tournoy
Dieter
D
Hartmann
Tobias
T
Huth
Kim
K
Cryns
Siska
S
Deforce
Lutgarde
L
Serneels
Ira Espuny
IE
Camacho
Els
E
Marjaux
Katleen
K
Craessaerts
Anton J M
AJ
Roebroek
Michael
M
Schwake
Rudi
R
D'Hooge
Patricia
P
Bach
Ulrich
U
Kalinke
Dieder
D
Moechars
Christian
C
Alzheimer
Karina
K
Reiss
Paul
P
Saftig
Bart
B
De Strooper
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology; D002478:Cells, Cultured; D004594:Electrophysiology; D010450:Endopeptidases; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D015222:Sodium Channels / Q000378:metabolism; D015996:Survival Rate
D016229:Amyloid beta-Peptides; D015222:Sodium Channels; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse