Erythrocytes as Biomarkers for Dementia: Analysis of Protein Content and Alpha-Synuclein

Abstract

Background: Discovering biomarkers for dementia is a pivotal step toward successful early diagnosis and treatment. Although plasma biomarkers have been explored, no consensus has been reached. Alpha-synuclein (AS), a 14 kDa synaptic protein associated with several neurodegenerative diseases, exists natively within erythrocytes (ERC). This protein is characteristic of Lewy body diseases, in which it aggregates into toxic Lewy bodies. As ERC are implicated in dementia, they are a potential target for future biomarkers. Objective: The aims of this study were to assess AS levels within ERC and whether AS can be used as a peripheral biomarker to differentiate between dementia and aged matched healthy control subjects. Methods: A total of 114 samples (60 aging controls, 36 Alzheimer's disease, 12 vascular dementia (VaD) and 6 dementia with Lewy bodies (DLB) subjects) were analyzed. We used Bradford assay to measure protein concentration, indirect ELISA to detect levels of AS, and immunoblotting to identify AS composition. Data were analyzed with nonparametric tests. Results: AS oligomers were present in dementia blood samples, whereas in controls, AS was largely monomeric. There was a significant increase in AS levels in DLB whole blood (p = 0.005; Kruskal-Wallis test), with a sensitivity and specificity of 100.0% and 93.9%. Protein concentrations in ERC isolated at pH 5.7 were significantly increased in dementia patients compared to controls (17.58 versus 40.33 g/ml; p ≤ 0.005; Mann-Whitney test). In the VaD group, the protein concentration in the pH5.7 ERC fraction had sensitivity and specificity of 91.7% and 62.1%. Conclusions: ERC protein concentration and AS levels have a potential for development of a novel diagnostic dementia blood test.

Loss of capillary pericytes and the blood–brain barrier in white matter in poststroke and vascular dementias and Alzheimer’s disease

“…Homogenates of tissue were prepared essentially as described previously for the multiplex cytokine assays (14). Fibrinogen was determined using a sandwich ELISA (25). PDGFR‐β was assayed as specified by the manufacturer (Human Total PDGFR beta DuoSet IC ELISA, DYC385, R&D Systems, Minneapolis, MN).…”

An attempt to dissect a peripheral marker based on cell pathology in Parkinson's disease

“…Several studies in the last two decades probed the amount of α-syn in the blood, CSF and other fluids including saliva as a feasible marker in PD (Vivacqua et al 2016 ; Wang et al 2015 ). These studies became more and more elaborated in detecting specific protein conformation and providing a significant correlation between PD and specific isoform of α-syn in various fluids (Majbour et al 2021 ; Wang et al 2015 ; Graham et al 2019 ). Again, since α-syn accumulation is related to an impairment of its metabolism which mainly takes place via the autophagy machinery (Petroi et al 2012 ; Limanaqi et al 2020 ; Langston and Cookson 2020 ), autophagy-related proteins were measured in PD patients (e.g., Wu et al 2011 ; Miki et al 2018 ).…”

Erythrocytes Are an Independent Protective Factor for Vascular Cognitive Impairment in Patients With Severe White Matter Hyperintensities

“…However, the effective components of erythrocytes in the central nervous system are not limited to Hb. The aforementioned cholinesterase activity, amyloid-β and α-synuclein are closely related to cognitive impairment (von Bernhardi et al, 2005;Lauriola et al, 2018;Graham et al, 2019).…”

“…Erythrocytes contain a large number of important biologically active media (such as cholinesterase activity, amyloid-β, αsynuclein, hydroxyoctadecadienoic acid, oxidatively modified peroxiredoxin, magnesium, catalase activity, and superoxide dismutase), which play important roles in the central nervous system through circulatory functions of their carrier (von Bernhardi et al, 2005;Yoshida et al, 2009;Lauriola et al, 2018;Graham et al, 2019;Sitzia et al, 2020). With the chronic effects of vascular risk factors or stroke events, the imbalance in these components in erythrocytes or alterations in membrane surface receptors are not only closely related to cognitive impairment but also are important potential predictors of the occurrence and development of VCI (von Bernhardi et al, 2005;Yoshida et al, 2009;Lauriola et al, 2018;Graham et al, 2019;Sitzia et al, 2020). Studies have found that in elderly patients, severe chronic anemia can increase white matter stroke by 1.8 times, which is an independent risk factor for stroke exacerbation and cognitive impairment (Inzitari et al, 2008;Hao et al, 2013).…”