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MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (22 February 2022) | Viewed by 58235

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Dr. Christian Barbato

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Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Via E. Ramarini, Monterotondo Scalo, 00015 Rome, Italy
Interests: NeuroCOVID-19; SARS-CoV-2; post-COVID-19 syndrome; microRNA; RNA-induced silencing complex (RISC); RNA-binding protein; neurodegenerative disease; Alzheimer’s disease; small non-coding RNA; RNA metabolism; cellular and molecular neurobiology; translational biomedicine
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Dear Colleagues,

The aim of this Special Issue entitled “MicroRNA-Mediated Silencing Pathways in the Nervous System and Brain Diseases” is to explore the recent developments on microRNAs (miRNAs) and RNA-induced silencing complex (RISC) in neurobiology and neurological diseases. MicroRNAs are a large family of conserved small, 20–22 nucleotides length, non-coding RNAs, widely expressed in all organisms and higly expressed in the mammalian nervous system. MiRNAs regulate neuronal gene expression at post-transcriptional level during neurogenesis, neurodevelopment, differentiation, morphogenesis of dendrites, synaptic plasticity, learning and memory. In the nervous system miRNAs play a pivotal role by their expression spatially and temporally modulated and regulating neural gene expression in physiological and pathological conditions. Moreover, miRNAs are involved in local protein synthesis tuning dendritic mRNA translation.

MiRNAs can silence target gene through Argonaute2 (Ago2), associating to form the RNA-induced silencing complex. In RNA interference pathway, RISC is fundamental in silencing of translation mechanisms and driving mRNA degradation.

Studies in mammalian models showed that RNA-induced silencing complexes and specific miRNAs might participate in synaptic plasticity processes supporting learning, memory and cognition, suggesting further exploration of RISC components in neurobiology models.

Significant progress has been made in our understanding of miRNAs in the nervous system and it provide an encouraging starting point to investigate miRNA pathway involvement in the development and progression of neurological and psychiatric diseases and to search future therapeutic applications. Original and review articles from this Special Issue will provide recent molecular and cellular neurobiological findings and traslational biomedicine studies that highlight the role of miRNAs in the nervous system in health and disease, mapping the geography of microRNA-mediated silencing pathways in the nervous system.

Dr. Christian Barbato
Guest Editor

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Keywords

microRNA
Ago2
RNA induced silencing complex (RISC)
RNA-binding protein
Small non-coding RNA
Neurological diseases
Neurodegenerative diseases
Alzheimer’s disease
Parkinson’s disease
neurodegeneration
aging
dementia
miRNA based therapy

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Published Papers (13 papers)

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Editorial

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3 pages, 194 KiB

Open AccessEditorial

MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases

by Christian Barbato

Cells 2022, 11(15), 2375; https://doi.org/10.3390/cells11152375 - 2 Aug 2022

Cited by 11 | Viewed by 1587

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs that play a prominent role in post-transcriptional gene regulation mechanisms in the brain tuning synaptic plasticity, memory formation, and cognitive functions in physiological and pathological conditions [...] Full article

(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)

Research

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16 pages, 3293 KiB

Open AccessArticle

Silencing of Ago-2 Interacting Protein SERBP1 Relieves KCC2 Repression by miR-92 in Neurons

by Christian Barbato, Paola Frisone, Laura Braccini, Simona D’Aguanno, Luisa Pieroni, Maria Teresa Ciotti, Caterina Catalanotto, Carlo Cogoni and Francesca Ruberti

Cells 2022, 11(6), 1052; https://doi.org/10.3390/cells11061052 - 20 Mar 2022

Cited by 6 | Viewed by 3934

Abstract

RNA-binding proteins (RBPs) play important roles in modulating miRNA-mediated mRNA target repression. Argonaute2 (Ago2) is an essential component of the RNA-induced silencing complex (RISC) that plays a central role in silencing mechanisms via small non-coding RNA molecules known as siRNAs and miRNAs. Small RNAs loaded into Argonaute proteins catalyze endoribonucleolytic cleavage of target RNAs or recruit factors responsible for translational silencing and mRNA target destabilization. In previous studies we have shown that KCC2, a neuronal Cl (−) extruding K (+) Cl (−) co-transporter 2, is regulated by miR-92 in neuronal cells. Searching for Ago2 partners by immunoprecipitation and LC-MS/MS analysis, we isolated among other proteins the Serpine mRNA binding protein 1 (SERBP1) from SH-SY5Y neuroblastoma cells. Exploring the role of SERBP1 in miRNA-mediated gene silencing in SH-SY5Y cells and primary hippocampal neurons, we demonstrated that SERBP1 silencing regulates KCC2 expression through the 3′ untranslated region (UTR). In addition, we found that SERBP1 as well as Ago2/miR-92 complex bind to KCC2 3′UTR. Finally, we demonstrated the attenuation of miR-92-mediated repression of KCC2 3′UTR by SERBP1 silencing. These findings advance our knowledge regarding the miR-92-mediated modulation of KCC2 translation in neuronal cells and highlight SERBP1 as a key component of this gene regulation. Full article

(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)

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21 pages, 3662 KiB

Open AccessArticle

Age-Dependent and Pathway-Specific Bimodal Action of Nicotine on Synaptic Plasticity in the Hippocampus of Mice Lacking the miR-132/212 Genes

by Tamara Stojanovic, David Velarde Gamez, Gabor Jorrid Schuld, Daniel Bormann, Maureen Cabatic, Pavel Uhrin, Gert Lubec and Francisco J. Monje

Cells 2022, 11(2), 261; https://doi.org/10.3390/cells11020261 - 13 Jan 2022

Cited by 5 | Viewed by 2983

Abstract

Nicotine addiction develops predominantly during human adolescence through smoking. Self-administration experiments in rodents verify this biological preponderance to adolescence, suggesting evolutionary-conserved and age-defined mechanisms which influence the susceptibility to nicotine addiction. The hippocampus, a brain region linked to drug-related memory storage, undergoes major morpho-functional restructuring during adolescence and is strongly affected by nicotine stimulation. However, the signaling mechanisms shaping the effects of nicotine in young vs. adult brains remain unclear. MicroRNAs (miRNAs) emerged recently as modulators of brain neuroplasticity, learning and memory, and addiction. Nevertheless, the age-dependent interplay between miRNAs regulation and hippocampal nicotinergic signaling remains poorly explored. We here combined biophysical and pharmacological methods to examine the impact of miRNA-132/212 gene-deletion (miRNA-132/212^−/−) and nicotine stimulation on synaptic functions in adolescent and mature adult mice at two hippocampal synaptic circuits: the medial perforant pathway (MPP) to dentate yrus (DG) synapses (MPP-DG) and CA3 Schaffer collaterals to CA1 synapses (CA3–CA1). Basal synaptic transmission and short-term (paired-pulse-induced) synaptic plasticity was unaltered in adolescent and adult miRNA-132/212^−/− mice hippocampi, compared with wild-type controls. However, nicotine stimulation promoted CA3–CA1 synaptic potentiation in mature adult (not adolescent) wild-type and suppressed MPP-DG synaptic potentiation in miRNA-132/212^−/− mice. Altered levels of CREB, Phospho-CREB, and acetylcholinesterase (AChE) expression were further detected in adult miRNA-132/212^−/− mice hippocampi. These observations propose miRNAs as age-sensitive bimodal regulators of hippocampal nicotinergic signaling and, given the relevance of the hippocampus for drug-related memory storage, encourage further research on the influence of miRNAs 132 and 212 in nicotine addiction in the young and the adult brain. Full article

(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)

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32 pages, 2696 KiB

Open AccessEditor’s ChoiceArticle

Co-Expression Analysis of microRNAs and Proteins in Brain of Alzheimer’s Disease Patients

by Callum N. Watson, Ghazala Begum, Emma Ashman, Daniella Thorn, Kamal M. Yakoub, Moustafa Al Hariri, Ali Nehme, Stefania Mondello, Firas Kobeissy, Antonio Belli and Valentina Di Pietro

Cells 2022, 11(1), 163; https://doi.org/10.3390/cells11010163 - 4 Jan 2022

Cited by 8 | Viewed by 3736

Abstract

Alzheimer’s disease (AD) is the most common form of dementia globally; however, the aetiology of AD remains elusive hindering the development of effective therapeutics. MicroRNAs (miRNAs) are regulators of gene expression and have been of growing interest in recent studies in many pathologies including AD not only for their use as biomarkers but also for their implications in the therapeutic field. In this study, miRNA and protein profiles were obtained from brain tissues of different stage (Braak III-IV and Braak V-VI) of AD patients and compared to matched controls. The aim of the study was to identify in the late stage of AD, the key dysregulated pathways that may contribute to pathogenesis and then to evaluate whether any of these pathways could be detected in the early phase of AD, opening new opportunity for early treatment that could stop or delay the pathology. Six common pathways were found regulated by miRNAs and proteins in the late stage of AD, with one of them (Rap1 signalling) activated since the early phase. MiRNAs and proteins were also compared to explore an inverse trend of expression which could lead to the identification of new therapeutic targets. These results suggest that specific miRNA changes could represent molecular fingerprint of neurodegenerative processes and potential therapeutic targets for early intervention. Full article

(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)

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21 pages, 4731 KiB

Open AccessArticle

Enhanced Expression of microRNA-1273g-3p Contributes to Alzheimer’s Disease Pathogenesis by Regulating the Expression of Mitochondrial Genes

by So Hee Kim, Kyu Yeong Choi, Yega Park, Catriona McLean, Jiyu Park, Jung Hoon Lee, Kyung-Hwa Lee, Byeong C. Kim, Yun Hyun Huh, Kun Ho Lee and Woo Keun Song

Cells 2021, 10(10), 2697; https://doi.org/10.3390/cells10102697 - 9 Oct 2021

Cited by 14 | Viewed by 3011

Abstract

Alzheimer’s disease (AD) is the most common form of dementia in the elderly population, but its underlying cause has not been fully elucidated. Recent studies have shown that microRNAs (miRNAs) play important roles in regulating the expression levels of genes associated with AD development. In this study, we analyzed miRNAs in plasma and cerebrospinal fluid (CSF) from AD patients and cognitively normal (including amyloid positive) individuals. miR-1273g-3p was identified as an AD-associated miRNA and found to be elevated in the CSF of early-stage AD patients. The overexpression of miR-1273g-3p enhanced amyloid beta (Aβ) production by inducing oxidative stress and mitochondrial impairments in AD model cell lines. A biotin-streptavidin pull-down assay demonstrated that miR-1273g-3p primarily interacts with mitochondrial genes, and that their expression is downregulated by miR-1273g-3p. In particular, the miR-1273g-3p-target gene TIMM13 showed reduced expression in brain tissues from human AD patients. These results suggest that miR-1273g-3p expression in an early stage of AD notably contributes to Aβ production and mitochondrial impairments. Thus, miR-1273g-3p might be a biomarker for early diagnosis of AD and a potential therapeutic target to prevent AD progression. Full article

(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)

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24 pages, 3396 KiB

Open AccessFeature PaperArticle

miRNA-132/212 Gene-Deletion Aggravates the Effect of Oxygen-Glucose Deprivation on Synaptic Functions in the Female Mouse Hippocampus

by Daniel Bormann, Tamara Stojanovic, Ana Cicvaric, Gabor J. Schuld, Maureen Cabatic, Hendrik Jan Ankersmit and Francisco J. Monje

Cells 2021, 10(7), 1709; https://doi.org/10.3390/cells10071709 - 6 Jul 2021

Cited by 6 | Viewed by 3947

Abstract

Cerebral ischemia and its sequelae, which include memory impairment, constitute a leading cause of disability worldwide. Micro-RNAs (miRNA) are evolutionarily conserved short-length/noncoding RNA molecules recently implicated in adaptive/maladaptive neuronal responses to ischemia. Previous research independently implicated the miRNA-132/212 cluster in cholinergic signaling and synaptic transmission, and in adaptive/protective mechanisms of neuronal responses to hypoxia. However, the putative role of miRNA-132/212 in the response of synaptic transmission to ischemia remained unexplored. Using hippocampal slices from female miRNA-132/212 double-knockout mice in an established electrophysiological model of ischemia, we here describe that miRNA-132/212 gene-deletion aggravated the deleterious effect of repeated oxygen-glucose deprivation insults on synaptic transmission in the dentate gyrus, a brain region crucial for learning and memory functions. We also examined the effect of miRNA-132/212 gene-deletion on the expression of key mediators in cholinergic signaling that are implicated in both adaptive responses to ischemia and hippocampal neural signaling. miRNA-132/212 gene-deletion significantly altered hippocampal AChE and mAChR-M1, but not α7-nAChR or MeCP2 expression. The effects of miRNA-132/212 gene-deletion on hippocampal synaptic transmission and levels of cholinergic-signaling elements suggest the existence of a miRNA-132/212-dependent adaptive mechanism safeguarding the functional integrity of synaptic functions in the acute phase of cerebral ischemia. Full article

(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)

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Review

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18 pages, 324 KiB

Open AccessReview

MicroRNA Networks in Cognition and Dementia

by Grace S. Blount, Layton Coursey and Jannet Kocerha

Cells 2022, 11(12), 1882; https://doi.org/10.3390/cells11121882 - 9 Jun 2022

Cited by 20 | Viewed by 4445

Abstract

The change from viewing noncoding RNA as “junk” in the genome to seeing it as a critical epigenetic regulator in almost every human condition or disease has forced a paradigm shift in biomedical and clinical research. Small and long noncoding RNA transcripts are now routinely evaluated as putative diagnostic or therapeutic agents. A prominent role for noncoding microRNAs in the central nervous system has uncovered promising new clinical candidates for dementia-related disorders, treatments for which currently remain elusive even as the percentage of diagnosed patients increases significantly. Cognitive decline is a core neurodegenerative process in Alzheimer’s Disease, Frontotemporal Dementia, Lewy body dementia, vascular dementia, Huntington’s Disease, Creutzfeldt–Jakob disease, and a significant portion of Parkinson’s Disease patients. This review will discuss the microRNA-associated networks which influence these pathologies, including inflammatory and viral-mediated pathways (such as the novel SARS-CoV-2 virus implicated in COVID-19), and their current status in clinical trials. Full article

(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)

18 pages, 1595 KiB

Open AccessReview

The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis

by Jinmeng Liu, Fenghua Zhou, Yingjun Guan, Fandi Meng, Zhenhan Zhao, Qi Su, Weiwei Bao, Xuemei Wang, Jiantao Zhao, Zijun Huo, Lingyun Zhang, Shuanhu Zhou, Yanchun Chen and Xin Wang

Cells 2022, 11(3), 572; https://doi.org/10.3390/cells11030572 - 7 Feb 2022

Cited by 31 | Viewed by 6947

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects upper and lower motor neurons. As there is no effective treatment for ALS, it is particularly important to screen key gene therapy targets. The identifications of microRNAs (miRNAs) have completely changed the traditional view of gene regulation. miRNAs are small noncoding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression. Recent advances also indicate that miRNAs are biomarkers in many diseases, including neurodegenerative diseases. In this review, we summarize recent advances regarding the mechanisms underlying the role of miRNAs in ALS pathogenesis and its application to gene therapy for ALS. The potential of miRNAs to target diverse pathways opens a new avenue for ALS therapy. Full article

(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)

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37 pages, 1971 KiB

Open AccessReview

MicroRNAs in the Onset of Schizophrenia

by Kristen T. Thomas and Stanislav S. Zakharenko

Cells 2021, 10(10), 2679; https://doi.org/10.3390/cells10102679 - 6 Oct 2021

Cited by 27 | Viewed by 7094

Abstract

Mounting evidence implicates microRNAs (miRNAs) in the pathology of schizophrenia. These small noncoding RNAs bind to mRNAs containing complementary sequences and promote their degradation and/or inhibit protein synthesis. A single miRNA may have hundreds of targets, and miRNA targets are overrepresented among schizophrenia-risk genes. Although schizophrenia is a neurodevelopmental disorder, symptoms usually do not appear until adolescence, and most patients do not receive a schizophrenia diagnosis until late adolescence or early adulthood. However, few studies have examined miRNAs during this critical period. First, we examine evidence that the miRNA pathway is dynamic throughout adolescence and adulthood and that miRNAs regulate processes critical to late neurodevelopment that are aberrant in patients with schizophrenia. Next, we examine evidence implicating miRNAs in the conversion to psychosis, including a schizophrenia-associated single nucleotide polymorphism in MIR137HG that is among the strongest known predictors of age of onset in patients with schizophrenia. Finally, we examine how hemizygosity for DGCR8, which encodes an obligate component of the complex that synthesizes miRNA precursors, may contribute to the onset of psychosis in patients with 22q11.2 microdeletions and how animal models of this disorder can help us understand the many roles of miRNAs in the onset of schizophrenia. Full article

(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)

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24 pages, 1945 KiB

Open AccessReview

MicroRNAs in Prion Diseases—From Molecular Mechanisms to Insights in Translational Medicine

by Danyel Fernandes Contiliani, Yasmin de Araújo Ribeiro, Vitor Nolasco de Moraes and Tiago Campos Pereira

Cells 2021, 10(7), 1620; https://doi.org/10.3390/cells10071620 - 29 Jun 2021

Cited by 13 | Viewed by 5080

Abstract

MicroRNAs (miRNAs) are small non-coding RNA molecules able to post-transcriptionally regulate gene expression via base-pairing with partially complementary sequences of target transcripts. Prion diseases comprise a singular group of neurodegenerative conditions caused by endogenous, misfolded pathogenic (prion) proteins, associated with molecular aggregates. In humans, classical prion diseases include Creutzfeldt–Jakob disease, fatal familial insomnia, Gerstmann–Sträussler–Scheinker syndrome, and kuru. The aim of this review is to present the connections between miRNAs and prions, exploring how the interaction of both molecular actors may help understand the susceptibility, onset, progression, and pathological findings typical of such disorders, as well as the interface with some prion-like disorders, such as Alzheimer’s. Additionally, due to the inter-regulation of prions and miRNAs in health and disease, potential biomarkers for non-invasive miRNA-based diagnostics, as well as possible miRNA-based therapies to restore the levels of deregulated miRNAs on prion diseases, are also discussed. Since a cure or effective treatment for prion disorders still pose challenges, miRNA-based therapies emerge as an interesting alternative strategy to tackle such defying medical conditions. Full article

(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)

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23 pages, 2083 KiB

Open AccessReview

An Insight into the microRNAs Associated with Arteriovenous and Cavernous Malformations of the Brain

by Ioan Alexandru Florian, Andrei Buruiana, Teodora Larisa Timis, Sergiu Susman, Ioan Stefan Florian, Adrian Balasa and Ioana Berindan-Neagoe

Cells 2021, 10(6), 1373; https://doi.org/10.3390/cells10061373 - 2 Jun 2021

Cited by 13 | Viewed by 3982

Abstract

Background: Brain arteriovenous malformations (BAVMs) and cerebral cavernous malformations (CCMs) are rare developmental anomalies of the intracranial vasculature, with an irregular tendency to rupture, and as of yet incompletely deciphered pathophysiology. Because of their variety in location, morphology, and size, as well as unpredictable natural history, they represent a management challenge. MicroRNAs (miRNAs) are strands of non-coding RNA of around 20 nucleotides that are able to modulate the expression of target genes by binding completely or partially to their respective complementary sequences. Recent breakthroughs have been made on elucidating their contribution to BAVM and CCM occurrence, growth, and evolution; however, there are still countless gaps in our understanding of the mechanisms involved. Methods: We have searched the Medline (PubMed; PubMed Central) database for pertinent articles on miRNAs and their putative implications in BAVMs and CCMs. To this purpose, we employed various permutations of the terms and idioms: ‘arteriovenous malformation’, ‘AVM’, and ‘BAVM’, or ‘cavernous malformation’, ‘cavernoma’, and ‘cavernous angioma’ on the one hand; and ‘microRNA’, ‘miRNA’, and ‘miR’ on the other. Using cross-reference search; we then investigated additional articles concerning the individual miRNAs identified in other cerebral diseases. Results: Seven miRNAs were discovered to play a role in BAVMs, three of which were downregulated (miR-18a, miR-137, and miR-195*) and four upregulated (miR-7-5p, miR-199a-5p, miR-200b-3p, and let-7b-3p). Similarly, eight miRNAs were identified in CCM in humans and experimental animal models, two being upregulated (miR-27a and mmu-miR-3472a), and six downregulated (miR-125a, miR-361-5p, miR-370-3p, miR-181a-2-3p, miR-95-3p, and let-7b-3p). Conclusions: The following literature review endeavored to address the recent discoveries related to the various implications of miRNAs in the formation and growth of BAVMs and CCMs. Additionally, by presenting other cerebral pathologies correlated with these miRNAs, it aimed to emphasize the potential directions of upcoming research and biological therapies. Full article

(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)

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13 pages, 771 KiB

Open AccessReview

Small Activating RNAs: Towards the Development of New Therapeutic Agents and Clinical Treatments

by Hossein Ghanbarian, Shahin Aghamiri, Mohamad Eftekhary, Nicole Wagner and Kay-Dietrich Wagner

Cells 2021, 10(3), 591; https://doi.org/10.3390/cells10030591 - 8 Mar 2021

Cited by 19 | Viewed by 5484

Abstract

Small double-strand RNA (dsRNA) molecules can activate endogenous genes via an RNA-based promoter targeting mechanism. RNA activation (RNAa) is an evolutionarily conserved mechanism present in diverse eukaryotic organisms ranging from nematodes to humans. Small activating RNAs (saRNAs) involved in RNAa have been successfully used to activate gene expression in cultured cells, and thereby this emergent technique might allow us to develop various biotechnological applications, without the need to synthesize hazardous construct systems harboring exogenous DNA sequences. Accordingly, this thematic issue aims to provide insights into how RNAa cellular machinery can be harnessed to activate gene expression leading to a more effective clinical treatment of various diseases. Full article

(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)

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Other

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29 pages, 13990 KiB

Open AccessSystematic Review

Co-Expression Network Analysis of Micro-RNAs and Proteins in the Alzheimer’s Brain: A Systematic Review of Studies in the Last 10 Years

by Rachel Tasker, Joseph Rowlands, Zubair Ahmed and Valentina Di Pietro

Cells 2021, 10(12), 3479; https://doi.org/10.3390/cells10123479 - 9 Dec 2021

Cited by 9 | Viewed by 3950

Abstract

MicroRNAs (miRNAs) are small non-coding nucleic acids that can regulate post-transcriptional gene expression by binding to complementary sequences of target mRNA. Evidence showed that dysregulated miRNA expression may be associated with neurological conditions such as Alzheimer’s disease (AD). In this study, we combined the results of two independent systematic reviews aiming to unveil the co-expression network of miRNAs and proteins in brain tissues of AD patients. Twenty-eight studies including a total of 113 differentially expressed miRNAs (53 of them validated by qRT-PCR), and 26 studies including a total of 196 proteins differentially expressed in AD brains compared to healthy age matched controls were selected. Pathways analyses were performed on the results of the two reviews and 39 common pathways were identified. A further bioinformatic analysis was performed to match miRNA and protein targets with an inverse relation. This revealed 249 inverse relationships in 28 common pathways, representing new potential targets for therapeutic intervention. A meta-analysis, whenever possible, revealed miR-132-3p and miR-16 as consistently downregulated in late-stage AD across the literature. While no inverse relationships between miR-132-3p and proteins were found, miR-16′s inverse relationship with CLOCK proteins in the circadian rhythm pathway is discussed and therapeutic targets are proposed. The most significant miRNA dysregulated pathway highlighted in this review was the hippo signaling pathway with p = 1.66 × 10⁻⁹. Our study has revealed new mechanisms for AD pathogenesis and this is discussed along with opportunities to develop novel miRNA-based drugs to target these pathways. Full article

(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)

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