Endogenous Aβ peptide promote Aβ oligomerization tendency of spiked synthetic Aβ in Alzheimer's disease plasma

Abstract

Alzheimer's disease (AD) is the most common form of age-associated dementia. Several studies have predicted that AD is caused by the production and deposition of the β-amyloid peptide (Aβ) in the brain, which is one of pathologic hallmarks of AD. In particular, Aβ oligomers are reportedly the most toxic and pathogenic of other peptide forms. We previously developed Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ), a technique for measuring Aβ oligomerization in plasma to diagnose AD. Here, we clarified the molecular sizes of oligomers that can be detected by the MDS and investigated differences in plasma spiking with a synthetic Aβ peptide in the plasma of AD patients and individuals with non-AD neurological conditions. To determine Aβ oligomer sizes detectable by MDS, size exclusion chromatography (SEC) was first performed on incubated samples of synthetic Aβ42 peptides. As a result, no MDS signals were observed for the Aβ42 monomer fractions, but strong signals were found for oligomers of 7-35-mers long. Also, an amplified luminescent proximity homogeneous assay-linked immunoassay (AlphaLISA) was used to confirm that synthetic Aβ peptides not only recruited endogenous Aβ in plasma but also induced significantly stronger seeding in AD plasma than in healthy control plasma. In addition, the absence of the MDS signals in Aβ-depleted plasma confirmed that the increased oligomerization tendency in AD plasma is dependent on the presence of endogenous Aβ in plasma. Therefore, the MDS-OAβ measurement of oligomerization differences in plasma after incubation with spiked synthetic Aβ peptides has significant potential in AD diagnosis.

Keywords: Alzheimer's disease; Aβ peptides; Biomarker; Blood; Multimer detection system; Oligomer.