Circulating miRNA Biomarkers for Alzheimer's Disease

University of Melbourne, Australia
PLoS ONE (Impact Factor: 3.23). 07/2013; 8(7):e69807. DOI: 10.1371/journal.pone.0069807
Source: PubMed


A minimally invasive diagnostic assay for early detection of Alzheimer's disease (AD) is required to select optimal patient groups in clinical trials, monitor disease progression and response to treatment, and to better plan patient clinical care. Blood is an attractive source for biomarkers due to minimal discomfort to the patient, encouraging greater compliance in clinical trials and frequent testing. MiRNAs belong to the class of non-coding regulatory RNA molecules of ∼22 nt length and are now recognized to regulate ∼60% of all known genes through post-transcriptional gene silencing (RNAi). They have potential as useful biomarkers for clinical use because of their stability and ease of detection in many tissues, especially blood. Circulating profiles of miRNAs have been shown to discriminate different tumor types, indicate staging and progression of the disease and to be useful as prognostic markers. Recently their role in neurodegenerative diseases, both as diagnostic biomarkers as well as explaining basic disease etiology has come into focus. Here we report the discovery and validation of a unique circulating 7-miRNA signature (hsa-let-7d-5p, hsa-let-7g-5p, hsa-miR-15b-5p, hsa-miR-142-3p, hsa-miR-191-5p, hsa-miR-301a-3p and hsa-miR-545-3p) in plasma, which could distinguish AD patients from normal controls (NC) with >95% accuracy (AUC of 0.953). There was a >2 fold difference for all signature miRNAs between the AD and NC samples, with p-values<0.05. Pathway analysis, taking into account enriched target mRNAs for these signature miRNAs was also carried out, suggesting that the disturbance of multiple enzymatic pathways including lipid metabolism could play a role in AD etiology.

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Available from: Yoshiya Oda
    • "↑ in AD 0.01 miR-101-3p ↑ in AD NS miR-15a-5p ↑ in AD 0·04 miR-20a-5p ↑ in AD 0.02 miR-93-5p ↑ in AD 0.03 miR-106b-5p ↑ in AD NS miR-18b-5p ↑ in AD 0·01 miR-106a-5p ↑ in AD 0.05 miR-1306-5p ↓ in AD 0·01 miR-582-5p ↑ in AD 0·01 miR-143-3p ↑ in AD 0·02 miR-335-5p ↑ in AD 0.02 miR-361-5p ↑ in AD 0.03 miR-424-5p ↑ in AD 0·01 miR-342-3p ↓ in AD 0·01 miR-15b-3p ↓ in AD 0.03 Panel of 16 miRNAs 0.87 0.77 – Kumar [9] 2013 miR-15b-5p * ↓ in AD <0.0001 0.85 0.88 0.96 miR-142-3p-3p ↓ in AD <0.0001 0.65 1.00 0.96 miR-191-5p ↓ in AD <0.0001 0.95 0.76 0.95 Let-7g-5p * ↓ in AD <0.0001 0.95 0.53 0.93 Let-7d-5p ↓ in AD <0.0001 0.75 0.88 0.92 miR-545-3p * ↓ in AD 0.01 0.20 0.88 0.74 miR-301a-3p ↓ in AD NS – – – Combination of 3 miRNAs ( * ) 0.95 0.94 0.95 (Continued) "
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    ABSTRACT: Background: In recent years, microRNAs (miRNA), a class of non-coding RNA known to regulate protein expression post-transcriptionally, have been recognized as novel biomarkers of diseases. Objective: In this systematic review, we identify miRNAs that are differentially expressed in Alzheimer's disease (AD) and/or mild cognitive impairment (MCI) and evaluate their accuracy as potential blood biomarkers. Methods: Eligible studies of miRNAs in peripheral blood distinguishing patients with AD or MCI from cognitively normal controls were identified through standardized search strategies in Medline, PubMed, and Embase. MiRNAs that were differentially expressed were identified and where available their sensitivity and specificity for AD or MCI extracted from the retrieved studies. Results: Eighteen studies investigated the diagnostic value of miRNAs as peripheral biomarkers of AD/MCI. Twenty miRNAs were significantly upregulated and 32 miRNAs downregulated in AD compared to controls in ten AD studies. Nine miRNAs were consistently dysregulated in more than one study. Of the 8 MCI studies, only one miRNA, miR-132, was consistently upregulated in three independent studies. Of the studies that reported diagnostic accuracy data, the majority of miRNA panels and individual miRNAs had a sensitivity and specificity greater than 0.75. Conclusion: Individual studies suggest that microRNAs can differentiate patients with AD/MCI from cognitively normal controls with modest accuracy. However, the literature is constrained by methodological differences between studies, with few studies assessing the same miRNAs. To become potential biomarkers for AD, further studies with standardized study designs for replication and validation are required. Results from this review may help researchers select candidate miRNAs for further investigation.
    No preview · Article · Oct 2015 · Journal of Alzheimer's disease: JAD
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    • "In addition to being at an elevated risk of developing BD, the first-degree relatives of BD patients are also at an increased risk of developing schizophrenia and major depressive disorder (MDD) (Lichtenstein et al., 2009; Rasic et al., 2014), indicating a shared component to the aetiology of these psychiatric disorders. Altered gene expression has been identified in multiple studies of the blood and post-mortem brains of individuals with psychiatric disorders (Kumarasinghe et al., 2012; Seifuddin et al., 2013). Gene ontology analysis of these genes has implicated biological processes with apparent relevance to the pathogenesis of psychiatric illness such as synaptic function. "
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    ABSTRACT: Bipolar disorder (BD) is a highly heritable psychiatric disorder characterised by recurrent episodes of mania and depression. Many studies have reported altered gene expression in BD, some of which may be attributable to the dysregulated expression of miRNAs. Studies carried out to date have largely studied medicated patients, so it is possible that observed changes in miRNA expression might be a consequence of clinical illness or of its treatment. We sought to establish whether altered miRNA expression might play a causative role in the development of BD by studying young, unmedicated relatives of individuals with BD, who are at a higher genetic risk of developing BD themselves (high-risk individuals). The expression of 20 miRNAs previously implicated in either BD or schizophrenia was measured by qRT-PCR in whole-blood samples from 34 high-risk and 46 control individuals. Three miRNAs, miR-15b, miR-132 and miR-652 were up-regulated in the high-risk individuals, consistent with previous reports of increased expression of these miRNAs in patients with schizophrenia. Our findings suggest that the altered expression of these miRNAs might represent a mechanism of genetic susceptibility for BD. Moreover, our observation of altered miRNA expression in the blood prior to the onset of illness provides hope that one day blood-based tests may aid in the risk-stratification and treatment of BD. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Jan 2015 · Journal of Psychiatric Research
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    • "Similarly, miR-191 was shown to be a potential biomarker for early detection and severity of pulmonary hypertension (Wei et al., 2013). Remarkably, miR-191-5p was shown to be one of the best biomarker candidates to predict the Alzheimer’s disease with >95% accuracy (Kumar et al., 2013). miR-191 was also found to be significantly induced (3.79-fold, p < 0.0001) in nephrotic syndrome (NS) children making it a potential diagnostic marker for pediatric NS. "
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    ABSTRACT: Specific microRNAs have emerged as key players in disease biology by playing crucial role in disease development and progression. This review draws attention to one such microRNA, miR-191 that has been recently reported to be abnormally expressed in several cancers (>20) and various other diseases like diabetes-type 2, Crohn' s, pulmonary hypertension, and Alzheimer' s. It regulates important cellular processes such as cell proliferation, differentiation, apoptosis, and migration by targeting important transcription factors, chromatin remodelers, and cell cycle associated genes. Several studies have demonstrated it to be an excellent biomarker for cancer diagnosis and prognosis leading to two patents already in its kitty. In this first review we summarize the current knowledge of the regulation, functions and targets of miR-191 and discuss its potential as a promising disease biomarker and therapeutic target.
    Full-text · Article · Apr 2014 · Frontiers in Genetics
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