MicroRNA-455-3p as a Potential Biomarker for Alzheimer's Disease: An Update.

Subodh Kumar,P Hemachandra Reddy

doi:10.3389/fnagi.2018.00041

Abstract

A non-invasive and early-detectable peripheral biomarker is urgently needed for Alzheimer's disease (AD). The present study is a step forward to verify the biomarker properties of human microRNA-455-3p (Hsa-miR-455-3p) in AD patients. Our previous findings on mild cognitive impaired subjects, AD patients and AD cells and mouse models unveiled the miR-455-3p as a potential peripheral biomarker for AD. In the current study, we verified the differential expression of miR-455-3p in postmortem AD brains obtained from NIH NeuroBioBank, and fibroblasts and B-lymphocytes from both familial and sporadic AD patients from Coriell Cell Repository of National Institutes on Aging. Total RNA was extracted from the fibroblasts, B-lymphocytes and AD postmortem brains, and expression of miR-455-3p was measured by real-time reverse-transcriptase RT-PCR. Our real-time RT-PCR analysis showed a significant (P = 0.0002) upregulation of miR-455-3p expression in AD postmortem brains compared to healthy control samples. Expression of miR-455-3p was also upregulated in the fibroblasts from AD patients, however a significant difference in miR-455-3p level was observed in the cells from sporadic AD patients (P = 0.014) compared to healthy controls. Similarly, in B-lymphocytes, miR-455-3p level was also higher (P = 0.044) especially in sporadic AD cases compared to controls. Receiver operating characteristic (ROC) curve analysis indicated the significant area under ROC curve (AUROC) value of miR-455-3p in AD postmortem brain (AUROC = 0.792; P = 0.001) and AD fibroblasts cells (AUROC = 0.861; P = 0.03), whereas in B-lymphocytes AUROC value of miR-455-3p was not significant. Further, in-silico analysis for miRNA targets predictions showed the binding capacity of miR-455-3p with several AD associated key genes such as APP, NGF, USP25, PDRG1, SMAD4, UBQLN1, SMAD2, TP73, VAMP2, HSPBAP1, and NRXN1. Hence, these observations further revealed that miR-455-3p is a potential biomarker for AD and its possible therapeutic target for AD.

Highlights

Alzheimer’s disease (AD) is a progressive, heterogeneous, agedependent, neurodegenerative disorder, characterized by the loss of memory, impairment of multiple cognitive functions, and changes in the personality and behavior (Mattson, 2004; LaFerla et al, 2007; Reddy et al, 2010)
AD Postmortem Brains Total RNA was extracted from the postmortem brains of healthy controls (n = 15) and AD patients (n = 27) and expression of hsa-miR-455-3p was quantified by real-time RT-PCR analysis
AD Fibroblasts expression of miR-455-3p was quantified in the skin fibroblast cells generated form familial AD patients (n = 4), sporadic AD patients (n = 6), and healthy control subjects (n = 8)

Summary

Introduction

Alzheimer’s disease (AD) is a progressive, heterogeneous, agedependent, neurodegenerative disorder, characterized by the loss of memory, impairment of multiple cognitive functions, and changes in the personality and behavior (Mattson, 2004; LaFerla et al, 2007; Reddy et al, 2010). Morphological and pathological studies of postmortem AD brains revealed that AD is mainly associated with intracellular neurofibrillary tangles (NFTs); extracellular amyloid-β (Aβ) plaques; synaptic damage, loss of synapses, and loss of synaptic proteins; proliferation of reactive astrocytes and activated microglia; defects in cholinergic neurons; an age-dependent imbalance in hormones, and structural and functional changes in mitochondria (Terry et al, 1991; McGeer and McGeer, 1995; DeKosky et al, 1996; Nunomura et al, 2001; Reddy, 2006; Reddy and Beal, 2008; Du et al, 2010; Tampellini and Gouras, 2010; Swerdlow, 2011; Reddy et al, 2012; Zhu et al, 2013). The loss of synapses and synaptic damage are the best correlates of cognitive decline found in AD patients (Terry et al, 1991; Bertoni-Freddari et al, 1996; DeKosky et al, 1996)

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