Microglia in Neurodegeneration

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 46329

Special Issue Editor

Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy
Interests: neuron–glia interactions; microglia; brain physiopathology; exosomes; in vitro and in vivo models; epigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The role of microglia in brain physiology is becoming increasingly important, and it is now established that changes in their function are crucial in neurodegenerative diseases. Therefore, microglia has become an important target to try to counteract neurodegeneration. Many efforts have been made to identify the cellular, molecular, and epigenetic mechanisms underlying the involvement of microglia in neurodegeneration. In particular, attention has been focused on the phenotypic change of microglia from M2, neuroprotective, to M1, neurotoxic, in an attempt to find new potential therapeutic targets. Furthermore, the communication systems between microglia and other central nervous system cells, especially neurons, have been studied to identify alterations potentially involved in different neuropathological conditions, with the idea that the modulation of this communication through endogenous or exogenous biomolecules may modulate microglial phenotype and neurodegeneration. Therefore, this ”Microglia in Neurodegeneration” Special Issue aims to collect the most relevant and new research findings in the field, from (i) the identification and characterization of endogenous molecules and communication mechanisms involved in neuron–microglia crosstalk in physiopathological conditions, to (ii) the molecular and epigenetic mechanisms involved in microglial shift from M2 to M1 phenotype, and to (iii) the design and testing of molecules able to modulate neuron–microglia interactions and/or microglial phenotypic shift. With this Special Issue, we intend to collect and disseminate the most recent and innovative findings of this important research field. Furthermore, this is also a good opportunity for scientists of the field to show their recent works, both to other researchers of the field and to a wider audience of readers.

Prof. Dr. Barbara Monti
Guest Editor

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Keywords

  • neuron–microglia communication systems
  • released molecules and exosomes
  • microglial phenotypes
  • molecular and epigenetic mechanisms
  • drug design

Published Papers (8 papers)

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Research

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13 pages, 3055 KiB  
Article
Circulating Inflammatory miRNAs Associated with Parkinson’s Disease Pathophysiology
by Sara R. Oliveira, Pedro A. Dionísio, Leonor Correia Guedes, Nilza Gonçalves, Miguel Coelho, Mário M. Rosa, Joana D. Amaral, Joaquim J. Ferreira and Cecília M. P. Rodrigues
Biomolecules 2020, 10(6), 945; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10060945 - 23 Jun 2020
Cited by 31 | Viewed by 4056
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, being largely characterized by motor features. MicroRNAs (miRNAs) are small non-coding RNAs, whose deregulation has been associated with neurodegeneration in PD. In this study, miRNAs targeting cell death and/or inflammation pathways were [...] Read more.
Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, being largely characterized by motor features. MicroRNAs (miRNAs) are small non-coding RNAs, whose deregulation has been associated with neurodegeneration in PD. In this study, miRNAs targeting cell death and/or inflammation pathways were selected and their expression compared in the serum of PD patients and healthy controls. We used two independent cohorts (discovery and validation) of 20 idiopathic PD patients (iPD) and 20 healthy controls each. We also analyzed an additional group of 45 patients with a mutation in the leucine-rich repeat kinase 2 (LRRK2) gene (LRRK2-PD). miRNA expression was determined using Taqman qRT-PCR and their performance to discriminate between groups was assessed by receiver operating characteristic (ROC) curve analysis. We found miR-146a, miR-335-3p, and miR-335-5p downregulated in iPD and LRRK2-PD patients versus controls in both cohorts. In addition, miR-155 was upregulated in LRRK2-PD compared to iPD patients showing an appropriate value of area under the ROC curve (AUC 0.80) to discriminate between the two groups. In conclusion, our study identified a panel of inflammatory related miRNAs differentially expressed between PD patients and healthy controls that highlight key pathophysiological processes and may contribute to improve disease diagnosis. Full article
(This article belongs to the Special Issue Microglia in Neurodegeneration)
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Review

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11 pages, 495 KiB  
Review
Microglial Potassium Channels: From Homeostasis to Neurodegeneration
by Germana Cocozza, Stefano Garofalo, Riccardo Capitani, Giuseppina D’Alessandro and Cristina Limatola
Biomolecules 2021, 11(12), 1774; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11121774 - 26 Nov 2021
Cited by 8 | Viewed by 2402
Abstract
The growing interest in the role of microglia in the progression of many neurodegenerative diseases is developing in an ever-expedited manner, in part thanks to emergent new tools for studying the morphological and functional features of the CNS. The discovery of specific biomarkers [...] Read more.
The growing interest in the role of microglia in the progression of many neurodegenerative diseases is developing in an ever-expedited manner, in part thanks to emergent new tools for studying the morphological and functional features of the CNS. The discovery of specific biomarkers of the microglia phenotype could find application in a wide range of human diseases, and creates opportunities for the discovery and development of tailored therapeutic interventions. Among these, recent studies highlight the pivotal role of the potassium channels in regulating microglial functions in physiological and pathological conditions such as Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis. In this review, we summarize the current knowledge of the involvement of the microglial potassium channels in several neurodegenerative diseases and their role as modulators of microglial homeostasis and dysfunction in CNS disorders. Full article
(This article belongs to the Special Issue Microglia in Neurodegeneration)
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23 pages, 1151 KiB  
Review
Microglial Extracellular Vesicles as Vehicles for Neurodegeneration Spreading
by Inês Dinis Aires, Teresa Ribeiro-Rodrigues, Raquel Boia, Magda Ferreira-Rodrigues, Henrique Girão, António Francisco Ambrósio and Ana Raquel Santiago
Biomolecules 2021, 11(6), 770; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11060770 - 21 May 2021
Cited by 29 | Viewed by 4485
Abstract
Microglial cells are the neuroimmune competent cells of the central nervous system. In the adult, microglia are responsible for screening the neuronal parenchyma searching for alterations in homeostasis. Chronic neuroinflammation plays a role in neurodegenerative disease. Indeed, microglia-mediated neuroinflammation is involved in the [...] Read more.
Microglial cells are the neuroimmune competent cells of the central nervous system. In the adult, microglia are responsible for screening the neuronal parenchyma searching for alterations in homeostasis. Chronic neuroinflammation plays a role in neurodegenerative disease. Indeed, microglia-mediated neuroinflammation is involved in the onset and progression of several disorders in the brain and retina. Microglial cell reactivity occurs in an orchestrated manner and propagates across the neural parenchyma spreading the neuroinflammatory signal from cell to cell. Extracellular vesicles are important vehicles of intercellular communication and act as message carriers across boundaries. Extracellular vesicles can be subdivided in several categories according to their cellular origin (apoptotic bodies, microvesicles and exosomes), each presenting, different but sometimes overlapping functions in cell communication. Mounting evidence suggests a role for extracellular vesicles in regulating microglial cell action. Herein, we explore the role of microglial extracellular vesicles as vehicles for cell communication and the mechanisms that trigger their release. In this review we covered the role of microglial extracellular vesicles, focusing on apoptotic bodies, microvesicles and exosomes, in the context of neurodegeneration and the impact of these vesicles derived from other cells in microglial cell reactivity. Full article
(This article belongs to the Special Issue Microglia in Neurodegeneration)
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28 pages, 1088 KiB  
Review
Epigenetics and Communication Mechanisms in Microglia Activation with a View on Technological Approaches
by Sabrina Petralla, Francesca De Chirico, Andrea Miti, Ottavia Tartagni, Francesca Massenzio, Eleonora Poeta, Marco Virgili, Giampaolo Zuccheri and Barbara Monti
Biomolecules 2021, 11(2), 306; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11020306 - 18 Feb 2021
Cited by 11 | Viewed by 4911
Abstract
Microglial cells, the immune cells of the central nervous system (CNS), play a crucial role for the proper brain development and function and in CNS homeostasis. While in physiological conditions, microglia continuously check the state of brain parenchyma, in pathological conditions, microglia can [...] Read more.
Microglial cells, the immune cells of the central nervous system (CNS), play a crucial role for the proper brain development and function and in CNS homeostasis. While in physiological conditions, microglia continuously check the state of brain parenchyma, in pathological conditions, microglia can show different activated phenotypes: In the early phases, microglia acquire the M2 phenotype, increasing phagocytosis and releasing neurotrophic and neuroprotective factors. In advanced phases, they acquire the M1 phenotype, becoming neurotoxic and contributing to neurodegeneration. Underlying this phenotypic change, there is a switch in the expression of specific microglial genes, in turn modulated by epigenetic changes, such as DNA methylation, histones post-translational modifications and activity of miRNAs. New roles are attributed to microglial cells, including specific communication with neurons, both through direct cell–cell contact and by release of many different molecules, either directly or indirectly, through extracellular vesicles. In this review, recent findings on the bidirectional interaction between neurons and microglia, in both physiological and pathological conditions, are highlighted, with a focus on the complex field of microglia immunomodulation through epigenetic mechanisms and/or released factors. In addition, advanced technologies used to study these mechanisms, such as microfluidic, 3D culture and in vivo imaging, are presented. Full article
(This article belongs to the Special Issue Microglia in Neurodegeneration)
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22 pages, 3123 KiB  
Review
Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries
by Bobbi Fleiss, Juliette Van Steenwinckel, Cindy Bokobza, Isabelle K. Shearer, Emily Ross-Munro and Pierre Gressens
Biomolecules 2021, 11(1), 99; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11010099 - 13 Jan 2021
Cited by 31 | Viewed by 4497
Abstract
Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, [...] Read more.
Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, cognitive, and/or behavioral deficits. Damage includes neuronal degeneration, selective loss of subclasses of interneurons, blocked maturation of oligodendrocyte progenitor cells leading to dysmyelination, axonopathy and very likely synaptopathy, leading to impaired connectivity. The nature and severity of changes vary according to the type and severity of insult and maturation stage of the brain. Microglial activation has been demonstrated almost ubiquitously in perinatal brain injuries and these responses are key cell orchestrators of brain pathology but also attempts at repair. These divergent roles are facilitated by a diverse suite of transcriptional profiles and through a complex dialogue with other brain cell types. Adding to the complexity of understanding microglia and how to modulate them to protect the brain is that these cells have their own developmental stages, enabling them to be key participants in brain building. Of note, not only do microglia help build the brain and respond to brain injury, but they are a key cell in the transduction of systemic inflammation into neuroinflammation. Systemic inflammatory exposure is a key risk factor for poor neurodevelopmental outcomes in preterm born infants. Based on these observations, microglia appear as a key cell target for neuroprotection in perinatal brain injuries. Numerous strategies have been developed experimentally to modulate microglia and attenuate brain injury based on these strong supporting data and we will summarize these. Full article
(This article belongs to the Special Issue Microglia in Neurodegeneration)
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26 pages, 1456 KiB  
Review
Microglia in Alzheimer’s Disease in the Context of Tau Pathology
by Juan Ramón Perea, Marta Bolós and Jesús Avila
Biomolecules 2020, 10(10), 1439; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10101439 - 14 Oct 2020
Cited by 57 | Viewed by 10939
Abstract
Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest [...] Read more.
Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer’s disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes (APOE, TREM2, and CD33) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation. Full article
(This article belongs to the Special Issue Microglia in Neurodegeneration)
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15 pages, 883 KiB  
Review
The Regulatory Role of IL-10 in Neurodegenerative Diseases
by Chiara Porro, Antonia Cianciulli and Maria Antonietta Panaro
Biomolecules 2020, 10(7), 1017; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10071017 - 09 Jul 2020
Cited by 84 | Viewed by 9711
Abstract
IL-10, an immunosuppressive cytokine, is considered an important anti-inflammatory modulator of glial activation, preventing inflammation-mediated neuronal degeneration under pathological conditions. In this narrative review, we summarize recent insights about the role of IL-10 in the neurodegeneration associated with neuroinflammation, in diseases such as [...] Read more.
IL-10, an immunosuppressive cytokine, is considered an important anti-inflammatory modulator of glial activation, preventing inflammation-mediated neuronal degeneration under pathological conditions. In this narrative review, we summarize recent insights about the role of IL-10 in the neurodegeneration associated with neuroinflammation, in diseases such as Multiple Sclerosis, Traumatic Brain Injury, Amyotrophic lateral sclerosis, Alzheimer’s Disease, and Parkinson’s Disease, focusing on the contribution of this cytokine not only in terms of protective action, but also as possibly responsible for clinical worsening. The knowledge of this double face of the same coin, regarding the biological role of the IL-10, could aid the development of targeted therapies useful for limiting neurodegenerative processes. Full article
(This article belongs to the Special Issue Microglia in Neurodegeneration)
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22 pages, 955 KiB  
Review
Extracellular Vesicles miRNA Cargo for Microglia Polarization in Traumatic Brain Injury
by Maria Antonietta Panaro, Tarek Benameur and Chiara Porro
Biomolecules 2020, 10(6), 901; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10060901 - 12 Jun 2020
Cited by 30 | Viewed by 4240
Abstract
Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide, and despite its high dissemination, effective pharmacotherapies are lacking. TBI can be divided into two phases: the instantaneous primary mechanical injury, which occurs at the moment of insult, [...] Read more.
Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide, and despite its high dissemination, effective pharmacotherapies are lacking. TBI can be divided into two phases: the instantaneous primary mechanical injury, which occurs at the moment of insult, and the delayed secondary injury, which involves a cascade of biological processes that lead to neuroinflammation. Neuroinflammation is a hallmark of both acute and chronic TBI, and it is considered to be one of the major determinants of the outcome and progression of disease. In TBI one of the emerging mechanisms for cell–cell communication involved in the immune response regulation is represented by Extracellular Vesicles (EVs). These latter are produced by all cell types and are considered a fingerprint of their generating cells. Exosomes are the most studied nanosized vesicles and can carry a variety of molecular constituents of their cell of origin, including microRNAs (miRNAs). Several miRNAs have been shown to target key neuropathophysiological pathways involved in TBI. The focus of this review is to analyze exosomes and their miRNA cargo to modulate TBI neuroinflammation providing new strategies for prevent long-term progression of disease. Full article
(This article belongs to the Special Issue Microglia in Neurodegeneration)
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