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

Abstract

There is accumulating evidence that soluble amyloid-beta (Abeta) 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) Abeta oligomers. Analysis of Abeta oligomers derived from synthetic Abeta 1-42, by size-exclusion chromatography (SEC), revealed that our ELISA specifically detected HMW Abeta 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 Abeta oligomers was greater than that for CSF Abeta x-42. Furthermore, the CSF levels of HMW Abeta oligomers showed a negative correlation with Mini-Mental State Examination scores in the AD/MCI group. We conclude that the CSF HMW Abeta 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 Abeta oligomers play a critical role in the pathogenesis and progression of AD.

Vibrational spectroscopy of biofluids for disease screening or diagnosis: translation from the laboratory to a clinical setting

“…The BAN50 SAS-ELISA has been shown to specifically detect high molecular weight Ab oligomers in CSF samples from patients with AD or mild cognitive impairment; these signals are significantly higher than those obtained from age-matched controls, as well as correlating negatively with scores obtained in the MMSE. These results indicate a possible role for the SAS-ELISA as a useful molecular diagnostic marker for AD, and perhaps a surrogate marker for disease severity [92]. Again, there is a real possibility to combine such endpoints with reagent-free spectrochemical endpoints; in fact, these latter technologies could allow for real-time measurements of emerging pathology, a major challenge in neurodegenerative disease.…”

Increased Detection of Aβ Oligomers in the Cerebrospinal Fluid of Alzheimer s Disease: Fact or Artifact?

“…Several years later, Georganopoulou et al [5] used monoclonal and polyclonal antibodies specific for so called amyloid-derived diffusible ligands (ADDLs): the detection of the immune-reaction product was amplified using a nanoparticle-based biobarcode assay to demonstrate that ADDLs (molecular weights between 17 and 42 kDa) are elevated significantly in AD patients compared to age-matched controls. Fukumoto et al [6] developed a novel enzyme-linked immunosorbent assay and demonstrated elevated levels of high molecular weight (HMW) Aβ oligomers of 45-to 90-KDa in the CSF of AD patients. Such HMW oligomers account however for a very small amount (<1%) of the total oligomer mixture in the CSF of AD patients, which is instead predominantly composed of low molecular weight (LMW) oligomers [6].…”

“…Fukumoto et al [6] developed a novel enzyme-linked immunosorbent assay and demonstrated elevated levels of high molecular weight (HMW) Aβ oligomers of 45-to 90-KDa in the CSF of AD patients. Such HMW oligomers account however for a very small amount (<1%) of the total oligomer mixture in the CSF of AD patients, which is instead predominantly composed of low molecular weight (LMW) oligomers [6].…”

“…Moreover, Sehlin et al [10] cast doubt as to whether the reported increased levels of Aβ oligomers in the CSF by Georganopoulou et al and Fukumoto et al [5,6] are true or due to the interference of the heterophilic antibodies (HA) in the detection of Aβ oligomer with ELISAs [10]. HA, i.e.…”

Effects of Peptides Derived from Terminal Modifications of the Aβ Central Hydrophobic Core on Aβ Fibrillization

“…Recently, extensive investigation of the aggregation pathway reveals that oligomeric assemblies and not mature fibrils are responsible for Aβ neurotoxicity (4)(5)(6)(7)(8)(9). Several approaches have been designed to target the Aβ assembly process in an effort to reduce toxic species in the brain.…”