title: BACE knockout mice are healthy despite lacking the primary beta-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, 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.
authors.affiliation: Department of Genomics, Pharmacia Corp., 301 Henrietta Street, Kalamazoo, MI 49007, USA. steven.l.roberds@pharmacia.com
authors.forename: S L
authors.initials: SL
authors.lastname: Roberds
authors.forename: J
authors.initials: J
authors.lastname: Anderson
authors.forename: G
authors.initials: G
authors.lastname: Basi
authors.forename: M J
authors.initials: MJ
authors.lastname: Bienkowski
authors.forename: D G
authors.initials: DG
authors.lastname: Branstetter
authors.forename: K S
authors.initials: KS
authors.lastname: Chen
authors.forename: S B
authors.initials: SB
authors.lastname: Freedman
authors.forename: N L
authors.initials: NL
authors.lastname: Frigon
authors.forename: D
authors.initials: D
authors.lastname: Games
authors.forename: K
authors.initials: K
authors.lastname: Hu
authors.forename: K
authors.initials: K
authors.lastname: Johnson-Wood
authors.forename: K E
authors.initials: KE
authors.lastname: Kappenman
authors.forename: T T
authors.initials: TT
authors.lastname: Kawabe
authors.forename: I
authors.initials: I
authors.lastname: Kola
authors.forename: R
authors.initials: R
authors.lastname: Kuehn
authors.forename: M
authors.initials: M
authors.lastname: Lee
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: R
authors.initials: R
authors.lastname: Motter
authors.forename: N F
authors.initials: NF
authors.lastname: Nichols
authors.forename: M
authors.initials: M
authors.lastname: Power
authors.forename: D W
authors.initials: DW
authors.lastname: Robertson
authors.forename: D
authors.initials: D
authors.lastname: Schenk
authors.forename: M
authors.initials: M
authors.lastname: Schoor
authors.forename: G M
authors.initials: GM
authors.lastname: Shopp
authors.forename: M E
authors.initials: ME
authors.lastname: Shuck
authors.forename: S
authors.initials: S
authors.lastname: Sinha
authors.forename: K A
authors.initials: KA
authors.lastname: Svensson
authors.forename: G
authors.initials: G
authors.lastname: Tatsuno
authors.forename: H
authors.initials: H
authors.lastname: Tintrup
authors.forename: J
authors.initials: J
authors.lastname: Wijsman
authors.forename: S
authors.initials: S
authors.lastname: Wright
authors.forename: L
authors.initials: L
authors.lastname: McConlogue
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001921:Brain / Q000201:enzymology* / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D046508:Culture Techniques; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse