Amyloid-beta-protein isoforms in brain of subjects with PS1-linked, beta APP-linked and sporadic Alzheimer disease.
To determine whether similar abnormalities of various soluble full-length and N-terminal truncated Abeta peptides occur in postmortem cerebral cortex of affected PS1 mutation carriers, we examined the amounts of two amyloid species ending at residue 40 or at residues 42(43) using sandwich ELISA systems. Our results indicate that PS1 mutations effect a dramatic accumulation in brain of the highly insoluble potentially neurotoxic long-tailed isoforms of the Abeta peptide such as Abeta1-42(43) and Abetax-42(43). This enhancing effect of PS1 mutation on Abetax-42(43) deposition was highly similar to that of a betaAPP mutation (Val717Ile) but the effects on Abetax-40 production were significantly different between these two causal genes. In contrast to previous studies of soluble Abeta in plasma and in supernatants from cultured fibroblasts of subjects with PS1 mutations, our studies also show that there is an increase in insoluble Abetax-40 peptides in brain of subjects with PS1 mutations.
Tamaoka
A
A
Department of Neurology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305, Japan.
Fraser
P E
PE
Ishii
K
K
Sahara
N
N
Ozawa
K
K
Ikeda
M
M
Saunders
A M
AM
Komatsuzaki
Y
Y
Sherrington
R
R
Levesque
G
G
Yu
G
G
Rogaeva
E
E
Shoji
S
S
Nee
L E
LE
Pollen
D A
DA
Hendriks
L
L
Martin
J J
JJ
Van Broeckhoven
C
C
Roses
A D
AD
Farrer
L A
LA
St George-Hyslop
P H
PH
Mori
H
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D001923:Brain Chemistry; D008040:Genetic Linkage; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics*; D008875:Middle Aged; D017354:Point Mutation; D053764:Presenilin-1; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D012995:Solubility
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D020033:Protein Isoforms