BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: Implications for Alzheimer's disease therapeutics

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major components of plaque, β-amyloid peptides (Aβs), are produced from amyloid precursor protein (APP) by the activity of β- and γ-secretases. β-secretase activity cleaves APP to define the N-terminus of the Aβ1-x peptides and, therefore, has been a long-sought therapeutic target for treatment of AD. The gene encoding a β-secretase for beta-site APP cleaving enzyme (BACE) was identified recently. However, it was not known whether BACE was the primary β-secretase in mammalian brain nor whether inhibition of β-secretase might have effects in mammals that would preclude its utility as a therapeutic target. In the work described herein, we generated two lines of BACE knockout mice and characterized them for pathology, β-secretase activity and Aβ production. These mice appeared to develop normally and showed no consistent phenotypic differences from their wild-type littermates, including overall normal tissue morphology and brain histochemistry, normal blood and urine chemistries, normal blood-cell composition, and no overt behavioral and neuromuscular effects. Brain and primary cortical cultures from BACE knockout mice showed no detectable β-secretase activity, and primary cortical cultures from BACE knockout mice produced much less Aβ from APP. The findings that BACE is the primary β-secretase activity in brain and that loss of β-secretase activity produces no profound phenotypic defects with a concomitant reduction in β-amyloid peptide clearly indicate that BACE is an excellent therapeutic target for treatment of AD.