Journal
JOURNAL OF NEUROCHEMISTRY
Volume 127, Issue 4, Pages 471-481Publisher
WILEY
DOI: 10.1111/jnc.12198
Keywords
Alzheimer's disease; BACE; myelination; zebrafish
Categories
Funding
- Sanger Institute Zebrafish Mutation Resource [LSHG-CT-2003-503496]
- European Commission
- Welcome Trust [WT 077047/Z/05/Z]
- Deutsche Forschungsgemeinschaft [SFB 596]
- NGFNplus
- European Research Council under the European Union [321366-Amyloid]
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Alzheimer's disease is the most frequent dementia. Pathologically, Alzheimer's disease is characterized by the accumulation of senile plaques composed of amyloid beta-peptide (A beta). Two proteases, beta- and gamma-secretase proteolytically generate A beta from its precursor, the beta-amyloid precursor protein (APP). Inhibition of beta-secretase, also referred to as beta-site APP cleaving enzyme (BACE1) or c-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.
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