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

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, beta -amyloid peptides (APs), are produced from amyloid precursor protein (APP) by the activity of beta- and gamma -secretases. beta -secretase activity cleaves APP to define the N-terminus of the A beta1-x peptides and, therefore, has been a long-sought therapeutic target for treatment of AD. The gene encoding a beta -secretase for beta-site APP cleaving enzyme (BACE) was identified recently. However, it was not known whether BACE was the primary beta -secretase in mammalian brain nor whether inhibition of beta -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, beta -secretase activity and A beta 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 beta -secretase activity, and primary cortical cultures from BACE knockout mice produced much less A beta from APP. The findings that BACE is the primary beta -secretase activity in brain and that loss of beta -secretase activity produces no profound phenotypic defects with a concomitant reduction in beta -amyloid peptide clearly indicate that BACE is an excellent therapeutic target for treatment of AD.