Human Molecular Genetics, 2001, Vol. 10, No. 12 1317-1324
© 2001 Oxford University Press
BACE knockout mice are healthy despite lacking the primary ß-secretase activity in brain: implications for Alzheimer’s disease therapeutics
Department of Genomics, 1Department of Cell and Molecular Biology, 2Department of Investigative Toxicology, 3Department of Pharmacology and 4Department of Neuroscience, Pharmacia Corp., 301 Henrietta Street, Kalamazoo, MI 49007, USA, 5Elan Pharmaceuticals, South San Francisco, CA 94080, USA and 6Artemis Pharmaceuticals GmbH, Koeln D-51063, Germany
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, ß-amyloid peptides (Aßs), are produced from amyloid precursor protein (APP) by the activity of ß- and 
-secretases. ß-secretase activity cleaves APP to define the N-terminus of the Aß1-x peptides and, therefore, has been a long- sought therapeutic target for treatment of AD. The gene encoding a ß-secretase for beta-site APP cleaving enzyme (BACE) was identified recently. However, it was not known whether BACE was the primary ß-secretase in mammalian brain nor whether inhibition of ß-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, ß-secretase activity and Aß 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 ß-secretase activity, and primary cortical cultures from BACE knockout mice produced much less Aß from APP. The findings that BACE is the primary ß-secretase activity in brain and that loss of ß-secretase activity produces no profound phenotypic defects with a concomitant reduction in ß-amyloid peptide clearly indicate that BACE is an excellent therapeutic target for treatment of AD.
+ These authors contributed equally to this work
To whom correspondence should be addressed. Tel: +1 616 833 1011; Fax: +1 616 833 3508; Email: steven.l.roberds@pharmacia.com
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