Abstract
BackgroundBecause of the increasing life expectancy in our society, aging-related neurodegenerative disorders are one of the main issues in global health. Most of these diseases are characterized by the deposition of misfolded proteins and a progressive cognitive decline. Among these diseases, Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the most common types of degenerative dementia. Although both show specific features, an important neuropathological and clinical overlap between them hampers their correct diagnosis. In this work, we identified molecular biomarkers aiming to improve the misdiagnosis between both diseases.MethodsPlasma extracellular vesicles (EVs) -from DLB, AD and healthy controls- were isolated using size-exclusion chromatography (SEC) and characterized by flow cytometry, Nanoparticle Tracking Analysis (NTA) and cryo-electron microscopy. Next Generation Sequencing (NGS) and related bibliographic search was performed and a selected group of EV-associated microRNAs (miRNAs) was analysed by qPCR.ResultsResults uncovered two miRNAs (hsa-miR-451a and hsa-miR-21-5p) significantly down-regulated in AD samples respect to DLB patients, and a set of four miRNAs (hsa-miR-23a-3p, hsa-miR-126-3p, hsa-let-7i-5p, and hsa-miR-151a-3p) significantly decreased in AD respect to controls. The two miRNAs showing decreased expression in AD in comparison to DLB provided area under the curve (AUC) values of 0.9 in ROC curve analysis, thus suggesting their possible use as biomarkers to discriminate between both diseases. Target gene analysis of these miRNAs using prediction online tools showed accumulation of phosphorylation enzymes, presence of proteasome-related proteins and genes involved in cell death among others.ConclusionOur data suggest that plasma-EV associated miRNAs may reflect a differential profile for a given dementia-related disorder which, once validated in larger cohorts of patients, could help to improve the differential diagnosis of DLB versus AD.
Highlights
Because of the increasing life expectancy in our society, aging-related neurodegenerative disorders are one of the main issues in global health
Focusing in the analysis of the 2 Micro RNA (miRNA) differentially expressed in Alzheimer’s disease (AD) vs dementia with Lewy bodies (DLB) and/or controls, hsa-miR-451a and hsa-miR-21-5p, we found an enrichment of genes related to SMAD protein phosphorylation (p = 3.810E-5)
cerebrospinal fluid (CSF) would be the ideal source for specific biomarkers of central nervous system disorders, the difficulty, invasiveness, morbidity, and risk related to CSFcollection have paved the way for the analysis of plasmaderived extracellular vesicles (EVs) in these pathologic scenarios
Summary
Because of the increasing life expectancy in our society, aging-related neurodegenerative disorders are one of the main issues in global health. Most of these diseases are characterized by the deposition of misfolded proteins and a progressive cognitive decline. Among these diseases, Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the most common types of degenerative dementia. Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the most common types of degenerative dementia Both show specific features, an important neuropathological and clinical overlap between them hampers their correct diagnosis. A high proportion of DLB cases are missed or misdiagnosed as AD, resulting in an incorrect treatment of the patient, which leads to the development of adverse reactions in 50% of these treated patients [7]
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