TY - JOUR

T1 - High-molecular-weight β-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients

AU - Fukumoto, Hiroaki

AU - Tokuda, Takahiko

AU - Kasai, Takashi

AU - Ishigami, Noriko

AU - Hidaka, Hiroya

AU - Kondo, Masaki

AU - Allsop, David

AU - Nakagawa, Masanori

PY - 2010

Y1 - 2010

N2 - There is accumulating evidence that soluble amyloid-β (Aβ) oligomers, rather than amyloid fibrils, are the principal pathogenic species in Alzheimer disease (AD). Here, we have developed a novel enzyme-linked immunosorbent assay (ELISA) specific for high-molecular-weight (HMW) Aβ oligomers. Analysis of Aβ oligomers derived from synthetic Aβ1-42, by size-exclusion chromatography (SEC), revealed that our ELISA specifically detected HMW Aβ oligomers of 40–200 kDa. Using this ELISA, we detected significantly higher (P<0.0001) signals in cerebrospinal fluid (CSF) samples from 25 patients with AD or mild cognitive impairment (MCI), compared to 25 age-matched controls. As a test for discriminating between the AD/MCI and control groups, the area under the curve in receiver operating characteristic analysis for the CSF HMW Aβ oligomers was greater than that for CSF Aβx-42. Furthermore, the CSF levels of HMW Aβ oligomers showed a negative correlation with Mini-Mental State Examination scores in the AD/MCI group. We conclude that the CSF HMW Aβ oligomers detected by our ELISA could be useful as a diagnostic marker for AD, and also as a potential surrogate marker for disease severity. Our results support the idea that soluble HMW Aβ oligomers play a critical role in the pathogenesis and progression of AD.—Fukumoto, H., Tokuda, T., Kasai, T., Ishigami, N., Hidaka, H., Kondo, M., Allsop, D., Nakagawa, M. High-molecular weight β-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients.

AB - There is accumulating evidence that soluble amyloid-β (Aβ) oligomers, rather than amyloid fibrils, are the principal pathogenic species in Alzheimer disease (AD). Here, we have developed a novel enzyme-linked immunosorbent assay (ELISA) specific for high-molecular-weight (HMW) Aβ oligomers. Analysis of Aβ oligomers derived from synthetic Aβ1-42, by size-exclusion chromatography (SEC), revealed that our ELISA specifically detected HMW Aβ oligomers of 40–200 kDa. Using this ELISA, we detected significantly higher (P<0.0001) signals in cerebrospinal fluid (CSF) samples from 25 patients with AD or mild cognitive impairment (MCI), compared to 25 age-matched controls. As a test for discriminating between the AD/MCI and control groups, the area under the curve in receiver operating characteristic analysis for the CSF HMW Aβ oligomers was greater than that for CSF Aβx-42. Furthermore, the CSF levels of HMW Aβ oligomers showed a negative correlation with Mini-Mental State Examination scores in the AD/MCI group. We conclude that the CSF HMW Aβ oligomers detected by our ELISA could be useful as a diagnostic marker for AD, and also as a potential surrogate marker for disease severity. Our results support the idea that soluble HMW Aβ oligomers play a critical role in the pathogenesis and progression of AD.—Fukumoto, H., Tokuda, T., Kasai, T., Ishigami, N., Hidaka, H., Kondo, M., Allsop, D., Nakagawa, M. High-molecular weight β-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients.

KW - Aged

KW - Aged, 80 and over

KW - Alzheimer Disease

KW - Amyloid beta-Peptides

KW - Biological Markers

KW - Case-Control Studies

KW - Enzyme-Linked Immunosorbent Assay

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Molecular Weight

KW - Protein Multimerization

U2 - 10.1096/fj.09-150359

DO - 10.1096/fj.09-150359

M3 - Journal article

C2 - 20339023

VL - 24

SP - 2716

EP - 2726

JO - The FASEB journal : official publication of the Federation of American Societies for Experimental Biology

JF - The FASEB journal : official publication of the Federation of American Societies for Experimental Biology

SN - 1530-6860

IS - 8

ER -