| Autor: |
Bebber, Frauke, Hruscha, Alexander, Willem, Michael, Schmid, Bettina, Haass, Christian |
| Předmět: |
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| Zdroj: |
Journal of Neurochemistry; Nov2013, Vol. 127 Issue 4, p471-481, 11p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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