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BACE knockout mice are healthy despite lacking the primary beta-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 (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.

Pubmed ID: 11406613

Authors

  • Roberds SL
  • Anderson J
  • Basi G
  • Bienkowski MJ
  • Branstetter DG
  • Chen KS
  • Freedman SB
  • Frigon NL
  • Games D
  • Hu K
  • Johnson-Wood K
  • Kappenman KE
  • Kawabe TT
  • Kola I
  • Kuehn R
  • Lee M
  • Liu W
  • Motter R
  • Nichols NF
  • Power M
  • Robertson DW
  • Schenk D
  • Schoor M
  • Shopp GM
  • Shuck ME
  • Sinha S
  • Svensson KA
  • Tatsuno G
  • Tintrup H
  • Wijsman J
  • Wright S
  • McConlogue L

Journal

Human molecular genetics

Publication Data

June 1, 2001

Associated Grants

None

Mesh Terms

  • Alzheimer Disease
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Animals
  • Aspartic Acid Endopeptidases
  • Brain
  • Cell Line
  • Cells, Cultured
  • Culture Techniques
  • Endopeptidases
  • Enzyme Inhibitors
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout