Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo.
Mutations in the presenilin 1 (PS1) and presenilin 2 genes cosegregate with the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. We now document that the Abeta1-42(43)/Abeta1-40 ratio in the conditioned media of independent N2a cell lines expressing three FAD-linked PS1 variants is uniformly elevated relative to cells expressing similar levels of wild-type PS1. Similarly, the Abeta1-42(43)/Abeta1-40 ratio is elevated in the brains of young transgenic animals coexpressing a chimeric amyloid precursor protein (APP) and an FAD-linked PS1 variant compared with brains of transgenic mice expressing APP alone or transgenic mice coexpressing wild-type human PS1 and APP. These studies provide compelling support for the view that one mechanism by which these mutant PS1 cause AD is by increasing the extracellular concentration of Abeta peptides terminating at 42(43), species that foster Abeta deposition.
Borchelt
D R
DR
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Thinakaran
G
G
Eckman
C B
CB
Lee
M K
MK
Davenport
F
F
Ratovitsky
T
T
Prada
C M
CM
Kim
G
G
Seekins
S
S
Yager
D
D
Slunt
H H
HH
Wang
R
R
Seeger
M
M
Levey
A I
AI
Gandy
S E
SE
Copeland
N G
NG
Jenkins
N A
NA
Price
D L
DL
Younkin
S G
SG
Sisodia
S S
SS
D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000235:genetics; D017077:Culture Media, Conditioned; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D009447:Neuroblastoma; D053764:Presenilin-1; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D017077:Culture Media, Conditioned; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011993:Recombinant Fusion Proteins