Loss of Bace2 in zebrafish affects melanocyte migration and is distinct from Bace1 knock out phenotypes
Article first published online: 11 MAR 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 127, Issue 4, pages 471–481, November 2013
How to Cite
J. Neurochem. (2013) 127, 471–481.
- Issue published online: 4 NOV 2013
- Article first published online: 11 MAR 2013
- Accepted manuscript online: 14 FEB 2013 12:31AM EST
- Manuscript Accepted: 12 FEB 2013
- Manuscript Revised: 25 JAN 2013
- Manuscript Received: 26 OCT 2012
- European Commission. Grant Number: LSHG-CT-2003–503496
- Welcome Trust. Grant Number: WT 077047/Z/05/Z
- Deutsche Forschungsgemeinschaft. Grant Number: SFB 596
- European Union's Seventh Framework Programme. Grant Number: FP7/2007-2013
- Alzheimer's disease;
- BACE ;
Alzheimer's disease is the most frequent dementia. Pathologically, Alzheimer's disease is characterized by the accumulation of senile plaques composed of amyloid β-peptide (Aβ). Two proteases, β- and γ-secretase proteolytically generate Aβ from its precursor, the ß-amyloid precursor protein (APP). Inhibition of β-secretase, also referred to as beta-site APP cleaving enzyme (BACE1) or γ-secretase is therefore of prime interest for the development of amyloid-lowering drugs. To assess the in vivo function of zebrafish Bace1 (zBace1), we generated zBace1 knock out fish by zinc finger nuclease-mediated genome editing. bace1 mutants (bace1−/−) are hypomyelinated in the PNS while the CNS is not affected. Moreover, the number of mechanosensory neuromasts is elevated in bace1−/−. Mutations in zebrafish Bace2 (zBace2) revealed a distinct melanocyte migration phenotype, which is not observed in bace1−/−. Double homozygous bace1−/−; bace2−/− fish do not enhance the single mutant phenotypes indicating non-redundant distinct physiological functions. Single homozygous bace1 mutants as well as double homozygous bace1 and bace2 mutants are viable and fertile suggesting that Bace1 is a promising drug target without major side effects. The identification of a specific bace2 −/− associated phenotype further allows improving selective Bace1 inhibitors and to distinguish between Bace 1 and Bace 2 inhibition in vivo.
Inhibition of BACE1 protease activity has therapeutic importance for Alzheimer's disease. Analysis of BACE1 and BACE2 knock-out zebrafish revealed that they exhibit distinct phenotypes. bace1 mutants display hypomyelination in the PNS and supernumerary neuromasts while in bace2 mutants the shape and migration of melanocytes is affected. These phenotypes are not further enhanced in the viable double mutants. Our data suggest that blocking BACE1 activity is a safe therapeutic approach.