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

Diana Dominguez,Els Marjaux,Kim Cryns,Siska Deforce,Katleen Craessaerts,Bart De Strooper,Christian Alzheimer,Michael Schwake,Jos Tournoy,Patricia Bach,Dieder Moechars,Lutgarde Serneels,Dieter Hartmann,Ulrich Kalinke,Tobias Huth,Anton A.j.m Roebroek ,Paul Säftig ,Karina Reiß ,Rudi D’hooge ,Ira Espuny-Camacho

doi:10.1074/jbc.m505249200

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.

Highlights

␤-Secretase (BACE1) is the rate-limiting protease for the generation of the amyloid ␤-peptide (A␤) in Alzheimer disease
As glia are 10 times more abundant in brain compared with neurons, our data indicate that BACE2 could contribute to A␤ generation in the brains of Alzheimer disease and, in particular, Down syndrome patients
A␤ pool in brain, and it has even been suggested that BACE2mediated amyloid precursor protein (APP) cleavage might play a role in the development of Alzheimer disease (AD) in individuals carrying the Flemish familial AD mutation in APP [8] as well as in the AD-like disease associated with Down syndrome [12, 21]

Summary

Introduction

␤-Secretase (BACE1) is the rate-limiting protease for the generation of the amyloid ␤-peptide (A␤) in Alzheimer disease. The BACE1-deficient mice surviving to adulthood were fertile, and histological and anatomical examination failed to evidence any gross phenotypic abnormality (supplemental Fig. 4) (data not shown). In the open field test, bace1 null mice displayed hyperactivity and enhanced locomotion compared with heterozygous and wild-type littermates, as illustrated by a significant increase in total move time (F(2,66) ϭ 10.743, p Ͻ 0.001) (Fig. 2A) and total distance traveled (H ϭ 16.387, p Ͻ 0.05) (Fig. 2B).

Results

Conclusion