BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes.
BACE1 is a key enzyme in the generation of Abeta, the major component of senile plaques in the brains of Alzheimer's disease patients. We have generated transgenic mice expressing human BACE1 with the Cam Kinase II promoter driving neuronal-specific expression. The transgene contains the full-length coding sequence of human BACE1 preceding an internal ribosome entry site element followed by a LacZ reporter gene. These animals exhibit a bold, exploratory behavior and show elevated 5-hydroxytryptamine turnover. We have also generated a knockout mouse in which LacZ replaces the first exon of murine BACE1. Interestingly these animals show a contrasting behavior, being timid and less exploratory. Despite these clear differences both mouse lines are viable and fertile with no changes in morbidity. These results suggest an unexpected role for BACE1 in neurotransmission, perhaps through changes in amyloid precursor protein processing and Abeta levels.
Harrison
Steve M
SM
Department of Comparative Genomics, GlaxoSmithKline, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, UK.
Harper
Alex J
AJ
Hawkins
Julie
J
Duddy
Graham
G
Grau
Evelyn
E
Pugh
Pippa L
PL
Winter
Panida H
PH
Shilliam
Claire S
CS
Hughes
Zoë A
ZA
Dawson
Lee A
LA
Gonzalez
M Isabel
MI
Upton
Neil
N
Pangalos
Menelas N
MN
Dingwall
Colin
C
D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency* / Q000235:genetics; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D010450:Endopeptidases; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D017930:Genes, Reporter / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics; D019076:Transgenes / Q000235:genetics
D016229:Amyloid beta-Peptides; D012701:Serotonin; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse