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Cited by 359

The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.

Phenotypic and Biochemical Analyses of BACE1- and BACE2-deficient Mice

Open access
Dominguez, Diana, Tournoy, Jos, Hartmann, Dieter, Huth, Tobias, Cryns, Kim, Deforce, Siska, Serneels, Lutgarde, Camacho, Ira Espuny, Marjaux, Els, Craessaerts, Katleen, Roebroek, Anton J.M., Schwake, Michael, D'Hooge, Rudi, Bach, Patricia, Kalinke, Ulrich, Moechars, Dieder, Alzheimer, Christian, Reiss, Karina, Saftig, Paul, De Strooper, Bart·2005·Journal of Biological Chemistry
DOI 10.1074/jbc.m505249200
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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.

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Metadata

Authors
Dominguez, D., Tournoy, J., Hartmann, D., Huth, T., Cryns, K., Deforce, S., Serneels, L., Camacho, I. E., Marjaux, E., Craessaerts, K., Roebroek, A. J. M., Schwake, M., D'Hooge, R., Bach, P., Kalinke, U., Moechars, D., Alzheimer, C., Reiss, K., Saftig, P., & De Strooper, B.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2005-09
Volume
280
Issue
35
Pages
30797-30806
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m505249200
OpenAlex
W2023274935
Cited by
359
References
6
FWCI
10.04
Type
journal article
Language
en
Open access
hybrid

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