Oligomeric alpha-synuclein and beta-amyloid variants as potential biomarkers for Parkinson's and Alzheimer's diseases

Oligomeric forms of alpha-synuclein and beta-amyloid are toxic protein variants that are thought to contribute to the onset and progression of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively. The detection of toxic variants in human cerebrospinal fluid (CSF) and blood has great promise for facilitating early and accurate diagnoses of these devastating diseases. Two hurdles that have impeded the use of these protein variants as biomarkers are the availability of reagents that can bind the different variants and a sensitive assay to detect their very low concentrations. We previously isolated antibody-based reagents that selectively bind two different oligomeric variants of alpha-synuclein and two of beta-amyloid, and developed a phage-based capture enzyme-linked immunosorbent assay (ELISA) with subfemtomolar sensitivity to quantify their presence. Here, we used these reagents to show that these oligomeric alpha-synuclein variants are preferentially present in PD brain tissue, CSF and serum, and that the oligomeric b-amyloid variants are preferentially present in AD brain tissue, CSF, and serum. Some AD samples also had alpha-synuclein pathology and some PD samples also had beta-amyloid pathology, and, very intriguingly, these PD cases also had a history of dementia. Detection of different oligomeric alpha-synuclein and beta-amyloid species is an effective method for identifying tissue, CSF and sera from PD and AD samples, respectively, and samples that also contained early stages of other protein pathologies, indicating their potential value as blood-based biomarkers for neurodegenerative diseases.