APP717 missense mutation affects the ratio of amyloid beta protein species (A beta 1-42/43 and a beta 1-40) in familial Alzheimer's disease brain.
We have biochemically purified A beta from brains of two unrelated familial Alzheimer's disease (FAD) pedigrees with the APP717 mutation (Val-->Ile) and from two sporadic Alzheimer's disease (AD) brains and characterized them by means of mass spectrometry and enzyme-linked immunosorbent assay. We observed two types of amyloid beta protein (A beta), the short-tail form (A beta 1-40) and the long-tail form (A beta 1-42/43), in sporadic AD and FAD brains, and found that the ratio of the long-tail form of A beta (A beta 1-42/43) to total A beta was increased in FAD brains. These in vivo results were confirmed in vitro using cultured cells transfected with three kinds of APP cDNAs bearing the APP717 mutations (Val-->Ile, Gly, or Phe). Taken together with the hypothesis that A beta 1-42/43 functions as a "seed" that increases the kinetics of amyloid fibril formation (Jarrett, J. T., and Lansbury, P. T., Jr. (1993) Cell 73, 1055-1058), we conclude that the APP717 missense mutation does not create new A beta species but promotes the increased accumulation of A beta 1-42/43 in the brain, which results in the enhancement of amyloid fibril formation from soluble A beta. These findings provide a causal relationship between this FAD genotype and the pathological phenotype of A beta deposition and senile plaque formation.
Tamaoka
A
A
Department of Neurology, University of Tsukuba, Ibaraki, Japan.
Odaka
A
A
Ishibashi
Y
Y
Usami
M
M
Sahara
N
N
Suzuki
N
N
Nukina
N
N
Mizusawa
H
H
Shoji
S
S
Kanazawa
I
I
D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism*
C094559:APP717; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)