A specific enzyme-linked immunosorbent assay for measuring beta-amyloid protein oligomers in human plasma and brain tissue of patients with Alzheimer disease.
OBJECTIVE
To examine in vivo levels of beta-amyloid (Abeta) oligomers (oAbeta) vs monomeric Abeta in plasma and brain tissue of patients with sporadic and familial Alzheimer disease (AD) using a new enzyme-linked immunosorbent assay (ELISA) specific for oAbeta.


METHODS
To establish the oAbeta ELISA, the same N-terminal Abeta antibody was used for antigen capture and detection. Plasma and postmortem brain tissue from patients with AD and control subjects were systematically analyzed by conventional monomeric Abeta and new oAbeta ELISAs.


METHODS
We measured oAbeta species in plasma samples from 36 patients with clinically well-characterized AD and 10 control subjects. In addition, postmortem samples were obtained from brain autopsies of 9 patients with verified AD and 7 control subjects.


METHODS
Oligomeric Abeta and 4 monomeric Abeta species in plasma samples from patients with AD and control subjects were measured by ELISA.


RESULTS
The specificity of the oAbeta ELISA was validated with a disulfide-crossed-linked, synthetic Abeta(1-40)Ser26Cys dimer that was specifically detected before but not after the dissociation of the dimers in beta-mercaptoethanol. Plasma assays showed that relative oAbeta levels were closely associated with relative Abeta(42) monomer levels across all of the subjects. Analysis of sequential plasma samples from a subset of the patients with AD, including a patient with AD caused by a presenilin mutation, revealed decreases in both oAbeta and Abeta(42) monomer levels over a 1- to 2-year period. In brain tissue from 9 patients with AD and 7 control subjects, both oAbeta and monomeric Abeta(42) levels were consistently higher in the AD cases.


CONCLUSIONS
An oAbeta-specific ELISA reveals a tight link between oAbeta and Abeta(42) monomer levels in plasma and brain. Both forms can decline over time in plasma, presumably reflecting their increasing insolubility in the brain.
Xia
Weiming
W
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, HIM 616, 77 Ave Louis Pasteur, Boston, MA 02115, USA. wxia@rics.bwh.harvard.edu
Yang
Ting
T
Shankar
Ganesh
G
Smith
Imelda M
IM
Shen
Yong
Y
Walsh
Dominic M
DM
Selkoe
Dennis J
DJ
D000368:Aged; D000544:Alzheimer Disease / Q000097:blood* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000097:blood*; D000918:Antibody Specificity; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000032:analysis / Q000097:blood; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011108:Polymers / Q000032:analysis / Q000378:metabolism; D011237:Predictive Value of Tests; D012995:Solubility
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; D011108:Polymers; C075222:amyloid beta-protein (1-42)