title: Loss of Bace2 in zebrafish affects melanocyte migration and is distinct from Bace1 knock out phenotypes.
abstract: 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.
authors: German Center for Neurodegenerative Diseases (DZNE), Schillerstr, Munich, Germany; Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, Schillerstr, Munich, Germany.
authors: Frauke
authors: F
authors: van Bebber
authors: Alexander
authors: A
authors: Hruscha
authors: Michael
authors: M
authors: Willem
authors: Bettina
authors: B
authors: Schmid
authors: Christian
authors: C
authors: Haass
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D002465:Cell Movement; D055786:Gene Knockout Techniques; D007814:Larva / Q000235:genetics / Q000378:metabolism; D008544:Melanocytes / Q000502:physiology*; D023421:Models, Animal; D009154:Mutation; D010641:Phenotype; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D029961:Zebrafish Proteins; D053829:Amyloid Precursor Protein Secretases; C585420:BACE1 protein, zebrafish; C585421:BACE2 protein, zebrafish
keywords: Alzheimer's disease; BACE; myelination; zebrafish