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.
Roberds
S L
SL
Department of Genomics, Pharmacia Corp., 301 Henrietta Street, Kalamazoo, MI 49007, USA. steven.l.roberds@pharmacia.com
Anderson
J
J
Basi
G
G
Bienkowski
M J
MJ
Branstetter
D G
DG
Chen
K S
KS
Freedman
S B
SB
Frigon
N L
NL
Games
D
D
Hu
K
K
Johnson-Wood
K
K
Kappenman
K E
KE
Kawabe
T T
TT
Kola
I
I
Kuehn
R
R
Lee
M
M
Liu
W
W
Motter
R
R
Nichols
N F
NF
Power
M
M
Robertson
D W
DW
Schenk
D
D
Schoor
M
M
Shopp
G M
GM
Shuck
M E
ME
Sinha
S
S
Svensson
K A
KA
Tatsuno
G
G
Tintrup
H
H
Wijsman
J
J
Wright
S
S
McConlogue
L
L
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
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