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

Authors

  • S.L. Roberds
  • J. Anderson
  • G. Basi
  • M.J. Bienkowski
  • D.G. Branstetter
  • K.S. Chen
  • S.B. Freedman
  • N.L. Frigon
  • D. Games
  • K. Hu
  • K. Johnson-Wood
  • K.E. Kappenman
  • T.T. Kawabe
  • I. Kola
  • R. Kuehn
  • M. Lee
  • W. Liu
  • R. Motter
  • N.F. Nichols
  • M. Power
  • D.W. Robertson
  • D. Schenk
  • M. Schoor
  • GM. Shopp
  • M.E. Shuck
  • S. Sinha
  • K.A. Svensson
  • G. Tatsuno
  • H. Tintrup
  • J. Wijsman
  • S. Wright
  • L. McConlogue

Journal

  • Human Molecular Genetics

Citation

  • Hum Mol Genet 10 (12): 1317-1324

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, beta-amyloid peptides (Abetas), 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 Abeta1-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 Abeta 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 Abeta 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.


DOI

doi:10.1093/hmg/10.12.1317