Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.
To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta-protein (A beta) ending at A beta 42(43) in vivo, we performed a blinded comparison of plasma A beta levels in carriers of these mutations and controls. A beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A beta ending at A beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A beta 42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.
Scheuner
D
D
Department of Neuroscience, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Eckman
C
C
Jensen
M
M
Song
X
X
Citron
M
M
Suzuki
N
N
Bird
T D
TD
Hardy
J
J
Hutton
M
M
Kukull
W
W
Larson
E
E
Levy-Lahad
E
E
Viitanen
M
M
Peskind
E
E
Poorkaj
P
P
Schellenberg
G
G
Tanzi
R
R
Wasco
W
W
Lannfelt
L
L
Selkoe
D
D
Younkin
S
S
D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D005260:Female; D005347:Fibroblasts; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010446:Peptide Fragments / Q000097:blood; D053764:Presenilin-1; D053766:Presenilin-2
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017077:Culture Media, Conditioned; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)