Enhanced amyloidogenic processing of the beta-amyloid precursor protein in gene-targeted mice bearing the Swedish familial Alzheimer's disease mutations and a "humanized" Abeta sequence.
The processing of the beta-amyloid precursor protein (APP) in vivo has been characterized in a novel animal model that recapitulates, in part, the APP genotype of a familial form of Alzheimer's disease (AD). A gene-targeting strategy was used to introduce the Swedish familial AD mutations and convert mouse Abeta to the human sequence. The mutant APP is expressed at normal levels in brain, and cleavage at the mutant beta-secretase site is both accurate and enhanced. Furthermore, human Abeta production is significantly increased to levels 9-fold greater than those in normal human brain while nonamyloidogenic processing is depressed. The results on Abeta production extend similar findings obtained in cell culture to the brain of an animal and substantiate Abeta as a etiological factor in Swedish familial AD. These animals provide several distinguishing features over others created by conventional transgenic methodologies. The spatial and temporal expression patterns of human Abeta are expected to be faithfully reproduced because the gene encoding the mutant APP remains in its normal chromosomal context. Thus, the neuropathological consequences of human Abeta overproduction can be evaluated longitudinally in the absence of potential mitigating effects of APP overexpression or presence of the mouse Abeta peptide.
Reaume
A G
AG
Cephalon, Inc., West Chester, Pennsylvania 19380, USA.
Howland
D S
DS
Trusko
S P
SP
Savage
M J
MJ
Lang
D M
DM
Greenberg
B D
BD
Siman
R
R
Scott
R W
RW
D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001483:Base Sequence; D001923:Brain Chemistry / Q000235:genetics; D002678:Chimera; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000378:metabolism; D018390:Gene Targeting; D005838:Genotype; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D013548:Sweden / Q000453:epidemiology
D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse