Oligomeric α‐synuclein and β‐amyloid variants as potential biomarkers for Parkinson's and Alzheimer's diseases

Abstract

Oligomeric forms of alpha-synuclein and beta-amyloid are toxic protein variants thought to contribute to the onset and progression of Parkinson’s (PD) and Alzheimer’s (AD) diseases, respectively. Detection of toxic variants in human cerebrospinal fluid (CSF) and blood has great promise to facilitate 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 ELISA with sub-femtomolar sensitivity to quantify their presence. Here we used these reagents to show that these oligomeric alpha-synuclein variants are preferentially present in the PD brain tissue, CSF and sera and that the oligomeric beta-amyloid variants are preferentially present in the AD brain tissue, CSF and sera. 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 to identify tissue, CSF and sera from PD and AD samples, respectively and samples which also contained early stages of other protein pathologies, indicating their potential value as blood based biomarkers for neurodegenerative diseases.

Alpha‐synuclein RT‐QuIC in the CSF of patients with alpha‐synucleinopathies

“…The presence of a‐syn has been detected in biological fluids such as cerebrospinal fluid (CSF)4 and serum 5. The measurement of a‐syn concentrations in CSF by ELISAs has been proposed as a biomarker for a‐syn‐related disorders.…”

APP/Aβ structural diversity and Alzheimer's disease pathogenesis

“…These technologies permit the generation of antibody based (nanobody) reagents that preferentially differentiate toxic-disease associated variants of key neuronal proteins including Aβ, tau, TDP43 and α-synuclein [212–221]. In the case of Aβ, nanobodies revealed three conformationally distinct oligomeric variants that differentiate postmortem AD brain specimens from healthy or Parkinson’s disease cases [220,222–224]. These observations indicate that detection of disease related protein variants may be a powerful blood or CSF based biomarker tool for AD and related neurodegenerative diseases.…”

Subtype Specific CSF Biomarkers in Sporadic Creutzfeldt-Jakob Disease

“…Alpha-synuclein is an emerging, well conserved target which has been detected in biological fluids such as CSF and serum [56,57]. Recently, many reports demonstrate the elevated levels of alpha-synuclein in the CSF of CJD patients [58][59][60].…”