Distinguishable effects of presenilin-1 and APP717 mutations on amyloid plaque deposition.
Both APP and PS-1 are causal genes for early-onset familial Alzheimer's disease (AD) and their mutation effects on cerebral Abeta deposition in the senile plaques were examined in human brains of 29 familial AD (23 PS-1, 6 APP) cases and 14 sporadic AD cases in terms of Abeta40 and Abeta42. Abeta isoform data were evaluated using repeated measures analysis of variance which adjusted for within-subject measurement variation and confounding effects of individual APP and PS-1 mutations, age at onset, duration of illness and APOE genotype. We observed that mutations in both APP and PS-1 were associated with a significant increase of Abeta42 in plaques as been documented previously. In comparison to sporadic AD cases, both APP717 and PS-1 mutation cases had an increased density (measured as the number of plaques/mm(2)) and area (%) of Abeta42 plaques. However, we found an unexpected differential effect of PS-1 but not APP717 mutation cases. At least some of PS-1 but not APP717 mutation cases had the significant increase of density and area of Abeta40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of Abeta burden in a different fashion from APP717 mutations in their familial AD brains.
Ishii
K
K
Department of Molecular Biology, Tokyo Institute of Psychiatry, Tokyo, Japan
Lippa
C
C
Tomiyama
T
T
Miyatake
F
F
Ozawa
K
K
Tamaoka
A
A
Hasegawa
T
T
Fraser
P E
PE
Shoji
S
S
Nee
L E
LE
Pollen
D A
DA
St  George-Hyslop
P H
PH
Ii
K
K
Ohtake
T
T
Kalaria
R N
RN
Rossor
M N
MN
Lantos
P L
PL
Cairns
N J
NJ
Farrer
L A
LA
Mori
H
H
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D002452:Cell Count; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D053764:Presenilin-1
C094559:APP717; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)