Human microRNA (miR-20b-5p) modulates Alzheimer’s disease pathways and neuronal function, and a specific polymorphism close to the MIR20B gene influences Alzheimer’s biomarkers (original) (raw)
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The microrna-mediated regulation of proteins implicated in the pathogenesis of Alzheimer's Disease
2016
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the post-mortem deposition of amyloid-beta (Aβ) containing neuritic plaques and tau-loaded tangles. According to the amyloid hypothesis, the generation of Aβ via the cleavage of Aβ precursor protein (APP) by β-APP site-cleaving enzyme 1 (BACE1) is a causative step in the development of AD. Therefore, targeting the production and/or clearance of Aβ peptide (by Aβ-degrading enzymes such as Neprilysin) would help understand the disorder as well as serves as therapeutic potential to treat the disorder. MicroRNA are small, noncoding RNA capable of modulating protein expression by primarily targeting their 3'UTR. Therefore, identifying miRNA which target APP, BACE1 and Neprilysin (NEP) would elucidate the complicated regulatory mechanisms involved in protein turnover and provide novel drug targets. We identified miR-20b as a modulator of APP and soluble Aβ. We also identified the target site for miR-20b's binding on the APP 3'UTR. Further, miR-20b exerts influence on neuronal morphology, likely due to its APP reduction. We also identified miR-298 as a dual regulator of APP and BACE1 and confirmed miR-298's targeting of both 3'UTRs. We also showed that miR-298 overexpression reduced levels of both soluble Aβ40 and Aβ42 peptides. Additionally, we identified two SNPs in proximity to the MIR298 gene, which are associated with AD-related biomarkers. Based on these results, we showed miR-298 targets a specific isoform of tau by putatively binding a non-canonical target site on the MAPT 3'UTR. Finally, the insertion of the NEP 3'UTR into a reporter vector v increases reporter expression; suggesting regulatory elements targeting the 3'UTR. We subsequently identified miR-216 as reducing NEP 3'UTR-mediated luciferase activity. We also measured levels of NEP protein in various mammalian tissuesuch as rodent and human fetal tissue, and subsequently showed measurable Aβ levels in correlation with NEP expression. Therefore, herein, we have identified miRNA involved in the regulation of proteins implicated in the pathogenesis of AD.
Alzheimer's & Dementia, 2008
MicroRNAs have essential functional roles in brain development and neuronal specification but their roles in neurodegenerative diseases such as Alzheimer's disease (AD) is unknown. Using a sensitive qRT-PCR platform we identified regional and stage-specific deregulation of miRNA expression in AD patient brains. We used experimental validation in addition to literature to reveal how the deregulated brain microRNAs are biomarkers for known and novel pathways in AD pathogenesis related to amyloid processing, neurogenesis, insulin resistance, and innate immunity. We additionally recovered miRNAs from cerebrospinal fluid and discovered AD-specific miRNA changes consistent with their role as potential biomarkers of disease.
The Eminent Role of microRNAs in the Pathogenesis of Alzheimer's Disease
Frontiers in Aging Neuroscience, 2021
Alzheimer's disease (AD) is an irrevocable neurodegenerative condition characterized by the presence of senile plaques comprising amassed β-amyloid peptides (Aβ) and neurofibrillary tangles mainly comprising extremely phosphorylated Tau proteins. Recent studies have emphasized the role of microRNAs (miRNAs) in the development of AD. A number of miRNAs, namely, miR-200a-3p, miR-195, miR-338-5p, miR-34a-5p, miR-125b-5p, miR-132, miR-384, miR-339-5p, miR-135b, miR-425-5p, and miR-339-5p, have been shown to participate in the development of AD through interacting with BACE1. Other miRNAs might affect the inflammatory responses in the course of AD. Aberrant expression of several miRNAs in the plasma samples of AD subjects has been shown to have the aptitude for differentiation of AD subjects from healthy subjects. Finally, a number of AD-modifying agents affect miRNA profile in cell cultures or animal models. We have performed a comprehensive search and summarized the obtained data a...
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Scientific reports, 2016
MicroRNAs (miRNAs) serve as key post-transcriptional regulators of gene expression. Genetic variation in miRNAs and miRNA-binding sites may affect miRNA function and contribute to disease risk. Here, we investigated the extent to which variants within miRNA-related sequences could constitute a part of the functional variants involved in developing Alzheimer's disease (AD), using the largest available genome-wide association study of AD. First, among 237 variants in miRNAs, we found rs2291418 in the miR-1229 precursor to be significantly associated with AD (p-value = 6.8 × 10(-5), OR = 1.2). Our in-silico analysis and in-vitro miRNA expression experiments demonstrated that the variant's mutant allele enhances the production of miR-1229-3p. Next, we found miR-1229-3p target genes that are associated with AD and might mediate the miRNA function. We demonstrated that miR-1229-3p directly controls the expression of its top AD-associated target gene (SORL1) using luciferase report...
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Current Genomics, 2009
Understanding complex diseases such as sporadic Alzheimer disease (AD) has been a major challenge. Unlike the familial forms of AD, the genetic and environmental risks factors identified for sporadic AD are extensive. MicroR-NAs are one of the major noncoding RNAs that function as negative regulators to silence or suppress gene expression via translational inhibition or message degradation. Their discovery has evoked great excitement in biomedical research for their promise as potential disease biomarkers and therapeutic targets. Key microRNAs have been identified as essential for a variety of cellular events including cell lineage determination, proliferation, apoptosis, DNA repair, and cytoskeletal organization; most, if not all, acting to fine-tune gene expression at the post-transcriptional level in a host of cellular signaling networks. Dysfunctional microRNA-mediated regulation has been implicated in the pathogenesis of many disease states. Here, the current understanding of the role of miRNAs in the central nervous system is reviewed with emphasis on their impact on the etiopathogenesis of sporadic AD.
MicroRNAs Modulate the Pathogenesis of Alzheimer’s Disease: An In Silico Analysis in the Human Brain
Genes, 2020
MicroRNAs (miRNAs) are small RNAs involved in the post-transcriptional regulation of their target genes, causing a decrease in protein translation from the mRNA. Different miRNAs are found in the nervous system, where they are involved in its physiological functions, but altered miRNAs expression was also reported in neurodegenerative disorders, including Alzheimer’s disease (AD). AD is characterized by memory loss, cognitive function abnormalities, and various neuropsychiatric disturbances. AD hallmarks are amyloid β (Aβ) aggregates, called senile plaques, and neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein. In this study, we performed an in silico analysis to evaluate altered patterns of miRNAs expression in the brains of AD patients compared to healthy subjects. We found 12 miRNAs that were differentially expressed in AD compared to healthy individuals. These miRNAs have target genes involved in AD pathogenesis. In particular, some miRNAs influence Aβ pro...
The Role of microRNAs in Alzheimer's Disease and Their Therapeutic Potentials
MicroRNAs (miRNAs) are short, endogenous, non-coding RNAs that post-transcriptionally regulate gene expression by base pairing with mRNA targets. Altered miRNA expression profiles have been observed in several diseases, including neurodegeneration. Multiple studies have reported altered expressions of miRNAs in the brains of individuals with Alzheimer's disease (AD) as compared to those of healthy elderly adults. Some of the miRNAs found to be dysregulated in AD have been reported to correlate with neuropathological changes, including plaque and tangle accumulation, as well as altered expressions of species that are known to be involved in AD pathology. To examine the potentially pathogenic functions of several dysregulated miRNAs in AD, we review the current literature with a focus on the activities of ten miRNAs in biological pathways involved in AD pathogenesis. Comprehensive understandings of the expression profiles and activities of these miRNAs will illuminate their roles as potential therapeutic targets in AD brain and may lead to the discovery of breakthrough treatment strategies for AD.
Neurobiology of aging, 2014
MicroRNAs (miRNAs) are small, noncoding RNAs that function in complex networks to regulate protein expression. In the brain, they are involved in development and synaptic plasticity. In this study, we aimed to identify miRNAs with a differential expression in either hippocampus or cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients and age-matched nondemented control subjects using quantitative polymerase chain reaction. In hippocampus, we also differentiated between AD patients with an intermediate stage, according to Braak III/IV stage, and a late stage, characterized according to Braak VI stage. Eight selected miRNAs were analyzed in hippocampus, and the expression of miR-16, miR-34c, miR-107, miR-128a, and miR-146a were differentially regulated. In CSF, out of 8 selected miRNAs only miR-16 and miR-146a could be reliably detected. In addition, we identified an effect of blood contamination on the CSF levels of miR-16, miR-24, and miR-146a. For group comparisons, ...
The emerging role of microRNAs in Alzheimer's disease
Frontiers in Physiology, 2015
MicroRNAs (miRNAs) are small non-coding RNA which have been shown to regulate gene expression. The alteration ofmiRNAs expression has been associated with several pathological processes, including neurodegeneration. In the search for easily accessible and non-invasive biomarkers for Alzheimer's disease (AD) diagnosis and prognosis, circulating miRNAs are among the most promising candidates. Some of them have been consistently identified as AD-specific miRNAs and their targets also seem implicated in pathophysiological processes underlying AD. Here, we review the emerging role for miRNA in AD, giving an overview on general miRNAs biology, their implications in AD pathophysiology and their potential role as future biomarkers.
Scientific Reports, 2016
MicroRNAs have emerged as key factors in development, neurogenesis and synaptic functions in the central nervous system. In the present study, we investigated a pathophysiological significance of microRNA-188-5p (miR-188-5p) in Alzheimer's disease (AD). We found that oligomeric Aβ 1-42 treatment diminished miR-188-5p expression in primary hippocampal neuron cultures and that miR-188-5p rescued the Aβ 1-42-mediated synapse elimination and synaptic dysfunctions. Moreover, the impairments in cognitive function and synaptic transmission observed in 7-month-old five familial AD (5XFAD) transgenic mice, were ameliorated via viral-mediated expression of miR-188-5p. miR-188-5p expression was down-regulated in the brain tissues from AD patients and 5XFAD mice. The addition of miR-188-5p rescued the reduction in dendritic spine density in the primary hippocampal neurons treated with oligomeric Aβ 1-42 and cultured from 5XFAD mice. The reduction in the frequency of mEPSCs was also restored by addition of miR-188-5p. The impairments in basal fEPSPs and cognition observed in 7-month-old 5XFAD mice were ameliorated via the viral-mediated expression of miR-188-5p in the hippocampus. Furthermore, we found that miR-188 expression is CREB-dependent. Taken together, our results suggest that dysregulation of miR-188-5p expression contributes to the pathogenesis of AD by inducing synaptic dysfunction and cognitive deficits associated with Aβ-mediated pathophysiology in the disease. MicroRNAs are non-coding RNA molecules with a length of approximately 22 nucleotides, which serve as post-transcriptional regulators of gene expression 1,2. In the central nervous system, microRNAs have been shown to regulate development, survival, function and plasticity 3-5. MicroRNAs and their precursors exist in synaptic fractions along with components of the microRNA machinery 6 , where they are poised to regulate neurotransmission. Furthermore, dysfunction of microRNAs within neurons and alterations in microRNA expression have been associated with the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) 7,8. However, little is known regarding whether restoring or reversal of deregulated microRNAs is capable of counteracting deficits in cognitive or synaptic dysfunctions in AD. Since AD-mediated cognitive deficits have been postulated as synaptic by origin 9,10 , one area that has been extensively researched is the study of aberrant amyloid beta peptide 1-42 (Aβ 1-42)-mediated modulation of synaptic transmission and plasticity 11. The most extensively documented synaptic phenomenon in this regard is long-term potentiation (LTP), which is inhibited by overexpression of APP genes 12 and Aβ administration 13 .