Abstract
BackgroundThe Australian Imaging and Biomarker Lifestyle (AIBL) study of aging is designed to aid the discovery of biomarkers. The current study aimed to discover differentially expressed plasma proteins that could yield a blood-based screening tool for Alzheimer’s disease.MethodsThe concentration of proteins in plasma covers a vast range of 12 orders of magnitude. Therefore, to search for medium to low abundant biomarkers and elucidate mechanisms of AD, we immuno-depleted the most abundant plasma proteins and pre-fractionated the remaining proteins by HPLC, prior to two-dimensional gel electrophoresis. The relative levels of approximately 3400 protein species resolved on the 2D gels were compared using in-gel differential analysis with spectrally resolved fluorescent protein detection dyes (Zdyes™). Here we report on analysis of pooled plasma samples from an initial screen of a sex-matched cohort of 72 probable AD patients and 72 healthy controls from the baseline time point of AIBL.ResultsWe report significant changes in variants of apolipoprotein E, haptoglobin, α1 anti-trypsin, inter-α trypsin inhibitor, histidine-rich glycoprotein, and a protein of unknown identity. α1 anti-trypsin and α1 anti-chymotrypsin demonstrated plasma concentrations that were dependent on APOE ε4 allele dose. Our analysis also identified an association with the level of Vitamin D binding protein fragments and complement factor I with sex. We then conducted a preliminary validation study, on unique individual samples compared to the discovery cohort, using a targeted LC-MS/MS assay on a subset of discovered biomarkers. We found that targets that displayed a high degree of isoform specific changes in the 2D gels were not changed in the targeted MS assay which reports on the total level of the biomarker.ConclusionsThis demonstrates that further development of mass spectrometry assays is needed to capture the isoform complexity that exists in theses biological samples. However, this study indicates that a peripheral protein signature has potential to aid in the characterization of AD.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 60–80% of cases [1]
The cohort was divided into two groups; cognitively healthy individuals, and participants diagnosed with AD as defined by NINCDS-ADRDA criteria [44] and majority were confirmed by amyloid positron emission tomography (PET)
The AD cohort was significantly older by 9.8 years (AD group 79.6 ± 3.1 years, healthy controls (HC) group 69.8 ± 3.2 years, p = 0.0001) and the AD population was significantly enriched in the APOE ε4 allele (40%, AD; 13%, HC; p = 0.0001) as anticipated [48]
Summary
Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 60–80% of cases [1]. While AD is conceptually a brain disease, there is evidence of altered protein expression in the periphery This has been shown in several avenues of research, including AD related morphological, chemical and proteomic changes in red-blood cells [11,12,13,14], alterations of motility in white blood cells and changes in membrane fluidity in leukocytes [15,16,17], as well as reports of plasma biomarker panels [18,19,20,21,22,23,24]. Previous proteomics studies have detected significant changes in proteins found in plasma, serum and CSF in AD None of these studies have yielded accurate, specific and reproducible diagnostic markers for AD [25,26,27,28]. The current study aimed to discover differentially expressed plasma proteins that could yield a bloodbased screening tool for Alzheimer’s disease
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