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Special Issue "Microglia in Aging and Neurodegenerative Disease"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 September 2017

Special Issue Editors

Co-Guest Editor
Dr. Jillian Nissen

Pharmacological Sciences, Stony Brook University, USA
Website | E-Mail
Interests: microglia, autoimmune disease, gender differences, neurodegeneration
Guest Editor
Prof. Styliani-Anna E. Tsirka

Pharmacological Sciences, Stony Brook University, USA
Website | E-Mail
Interests: microglia, neuroimmune interactions, models of disease, neurodegeneration, innate immunity, crosstalk

Special Issue Information

Dear Colleagues,

Microglia, the immune-competent cells of the central nervous system (CNS), are dynamic and responsive to changes in their environment. They undergo an activation process, which renders them either pro-inflammatory or anti-inflammatory. Through the expression of cytokines, chemokines, and other factors, activated microglia have been implicated in the onset and progression of different neurodegenerative diseases. Their rapid responses to injury and changes in the CNS parenchyma that lead to neurodegeneration suggest that they could serve as markers of disease onset. Manipulation of microglial activation can affect the progression of these diseases and modify systemic inflammatory processes. The number of microglia increases in aged mice. Their accumulation and changes in signaling contribute to an accelerated cognitive decline, thus making microglia and their signaling pathways targets to potential therapeutic modifications.

In this Special Issue of IJMS, the focus will be on the roles that microglia play and how they communicate with other cells in the brain parenchyma, their morphology and changes in neurodegenerative situations, as well as in the aging and aged brain.

Prof. Styliani-Anna (Stella) E. Tsirka
Guest Editor
Dr. Jillian C. Nissen
Co-Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • microglia
  • inflammation
  • neuropathology
  • brain
  • spinal cord
  • activation

Published Papers (9 papers)

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Research

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Open AccessArticle Annexin-1 Mediates Microglial Activation and Migration via the CK2 Pathway during Oxygen–Glucose Deprivation/Reperfusion
Int. J. Mol. Sci. 2016, 17(10), 1770; doi:10.3390/ijms17101770
Received: 2 September 2016 / Revised: 11 October 2016 / Accepted: 18 October 2016 / Published: 22 October 2016
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Abstract
Annexin-1 (ANXA1) has shown neuroprotective effects and microglia play significant roles during central nervous system injury, yet the underlying mechanisms remain unclear. This study sought to determine whether ANXA1 regulates microglial response to oxygen–glucose deprivation/reperfusion (OGD/R) treatment and to clarify the downstream molecular
[...] Read more.
Annexin-1 (ANXA1) has shown neuroprotective effects and microglia play significant roles during central nervous system injury, yet the underlying mechanisms remain unclear. This study sought to determine whether ANXA1 regulates microglial response to oxygen–glucose deprivation/reperfusion (OGD/R) treatment and to clarify the downstream molecular mechanism. In rat hippocampal slices, OGD/R treatment enhanced the ANXA1 expression in neuron, the formyl peptide receptor (FPRs) expression in microglia, and the microglial activation in the CA1 region (cornu ammonis 1). These effects were reversed by the FPRs antagonist Boc1. The cell membrane currents amplitude of BV-2 microglia (the microglial like cell-line) was increased when treated with Ac2-26, the N-terminal peptide of ANXA1. Ac2-26 treatment enhanced BV-2 microglial migration whereas Boc1 treatment inhibited the migration. In BV-2 microglia, both the expression of the CK2 target phosphorylated α-E-catenin and the binding of casein kinase II (CK2) with α-E-catenin were elevated by Ac2-26, these effects were counteracted by the CK2 inhibitor TBB and small interfering (si) RNA directed against transcripts of CK2 and FPRs. Moreover, both TBB and siRNA-mediated inhibition of CK2 blocked Ac2-26-mediated BV-2 microglia migration. Our findings indicate that ANXA1 promotes microglial activation and migration during OGD/R via FPRs, and CK2 target α-E-catenin phosphorylation is involved in this process. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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Review

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Open AccessReview Molecular Imaging of Neuroinflammation in Neurodegenerative Dementias: The Role of In Vivo PET Imaging
Int. J. Mol. Sci. 2017, 18(5), 993; doi:10.3390/ijms18050993
Received: 9 March 2017 / Revised: 14 April 2017 / Accepted: 18 April 2017 / Published: 5 May 2017
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Abstract
Neurodegeneration elicits neuroinflammatory responses to kill pathogens, clear debris and support tissue repair. Neuroinflammation is a dynamic biological response characterized by the recruitment of innate and adaptive immune system cells in the site of tissue damage. Resident microglia and infiltrating immune cells partake
[...] Read more.
Neurodegeneration elicits neuroinflammatory responses to kill pathogens, clear debris and support tissue repair. Neuroinflammation is a dynamic biological response characterized by the recruitment of innate and adaptive immune system cells in the site of tissue damage. Resident microglia and infiltrating immune cells partake in the restoration of central nervous system homeostasis. Nevertheless, their activation may shift to chronic and aggressive responses, which jeopardize neuron survival and may contribute to the disease process itself. Positron Emission Tomography (PET) molecular imaging represents a unique tool contributing to in vivo investigating of neuroinflammatory processes in patients. In the present review, we first provide an overview on the molecular basis of neuroinflammation in neurodegenerative diseases with emphasis on microglia activation, astrocytosis and the molecular targets for PET imaging. Then, we review the state-of-the-art of in vivo PET imaging for neuroinflammation in dementia conditions associated with different proteinopathies, such as Alzheimer’s disease, frontotemporal lobar degeneration and Parkinsonian spectrum. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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Open AccessReview Molecular Targets for PET Imaging of Activated Microglia: The Current Situation and Future Expectations
Int. J. Mol. Sci. 2017, 18(4), 802; doi:10.3390/ijms18040802
Received: 31 January 2017 / Revised: 15 March 2017 / Accepted: 28 March 2017 / Published: 11 April 2017
PDF Full-text (308 KB) | HTML Full-text | XML Full-text
Abstract
Microglia, as cellular mediators of neuroinflammation, are implicated in the pathogenesis of a wide range of neurodegenerative diseases. Positron emission tomography (PET) imaging of microglia has matured over the last 20 years, through the development of radiopharmaceuticals targeting several molecular biomarkers of microglial
[...] Read more.
Microglia, as cellular mediators of neuroinflammation, are implicated in the pathogenesis of a wide range of neurodegenerative diseases. Positron emission tomography (PET) imaging of microglia has matured over the last 20 years, through the development of radiopharmaceuticals targeting several molecular biomarkers of microglial activation and, among these, mainly the translocator protein-18 kDa (TSPO). Nevertheless, current limitations of TSPO as a PET microglial biomarker exist, such as low brain density, even in a neurodegenerative setting, expression by other cells than the microglia (astrocytes, peripheral macrophages in the case of blood brain barrier breakdown), genetic polymorphism, inducing a variation for most of TSPO PET radiopharmaceuticals’ binding affinity, or similar expression in activated microglia regardless of its polarization (pro- or anti-inflammatory state), and these limitations narrow its potential interest. We overview alternative molecular targets, for which dedicated radiopharmaceuticals have been proposed, including receptors (purinergic receptors P2X7, cannabinoid receptors, α7 and α4β2 nicotinic acetylcholine receptors, adenosine 2A receptor, folate receptor β) and enzymes (cyclooxygenase, nitric oxide synthase, matrix metalloproteinase, β-glucuronidase, and enzymes of the kynurenine pathway), with a particular focus on their respective contribution for the understanding of microglial involvement in neurodegenerative diseases. We discuss opportunities for these potential molecular targets for PET imaging regarding their selectivity for microglia expression and polarization, in relation to the mechanisms by which microglia actively participate in both toxic and neuroprotective actions in brain diseases, and then take into account current clinicians’ expectations. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
Open AccessReview Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases
Int. J. Mol. Sci. 2017, 18(4), 785; doi:10.3390/ijms18040785
Received: 31 January 2017 / Revised: 31 March 2017 / Accepted: 4 April 2017 / Published: 7 April 2017
Cited by 1 | PDF Full-text (524 KB) | HTML Full-text | XML Full-text
Abstract
In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positron Emission Tomography (PET) imaging, using dedicated radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO). In this review, we emphasized the major advances made over the last 20 years, thanks to TSPO
[...] Read more.
In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positron Emission Tomography (PET) imaging, using dedicated radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO). In this review, we emphasized the major advances made over the last 20 years, thanks to TSPO PET imaging, to define the pathophysiological implication of microglia activation and neuroinflammation in neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. The extent and upregulation of TSPO as a molecular biomarker of activated microglia in the human brain is now widely documented in these pathologies, but its significance, and especially its protective or deleterious action regarding the disease’s stage, remains under debate. Thus, we exposed new and plausible suggestions to enhance the contribution of TSPO PET imaging for biomedical research by exploring microglia’s role and interactions with other cells in brain parenchyma. Multiplex approaches, associating TSPO PET radiopharmaceuticals with other biomarkers (PET imaging of cellular metabolism, neurotransmission or abnormal protein aggregates, but also other imaging modalities, and peripheral cytokine levels measurement and/or metabolomics analysis) was considered. Finally, the actual clinical impact of TSPO PET imaging as a routine biomarker of neuroinflammation was put into perspective regarding the current development of diagnostic and therapeutic strategies for neurodegenerative diseases. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
Open AccessReview Old Maids: Aging and Its Impact on Microglia Function
Int. J. Mol. Sci. 2017, 18(4), 769; doi:10.3390/ijms18040769
Received: 1 March 2017 / Revised: 27 March 2017 / Accepted: 28 March 2017 / Published: 5 April 2017
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Abstract
Microglia are highly active and vigilant housekeepers of the central nervous system that function to promote neuronal growth and activity. With advanced age, however, dysregulated inflammatory signaling and defects in phagocytosis impede their ability to perform the most essential of homeostatic functions, including
[...] Read more.
Microglia are highly active and vigilant housekeepers of the central nervous system that function to promote neuronal growth and activity. With advanced age, however, dysregulated inflammatory signaling and defects in phagocytosis impede their ability to perform the most essential of homeostatic functions, including immune surveillance and debris clearance. Microglial activation is one of the hallmarks of the aging brain and coincides with age-related neurodegeneration and cognitive decline. Age-associated microglial dysfunction leads to cellular senescence and can profoundly alter the response to sterile injuries and immune diseases, often resulting in maladaptive responses, chronic inflammation, and worsened outcomes after injury. Our knowledge of microglia aging and the factors that regulate age-related microglial dysfunction remain limited, as the majority of pre-clinical studies are performed in young animals, and human brain samples are difficult to obtain quickly post-mortem or in large numbers. This review outlines the impact of normal aging on microglial function, highlights the potential mechanisms underlying age-related changes in microglia, and discusses how aging can shape the recovery process following injury. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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Open AccessReview Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging
Int. J. Mol. Sci. 2017, 18(3), 598; doi:10.3390/ijms18030598
Received: 31 January 2017 / Revised: 28 February 2017 / Accepted: 5 March 2017 / Published: 9 March 2017
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Abstract
Autophagy is emerging as a core regulator of Central Nervous System (CNS) aging and neurodegeneration. In the brain, it has mostly been studied in neurons, where the delivery of toxic molecules and organelles to the lysosome by autophagy is crucial for neuronal health
[...] Read more.
Autophagy is emerging as a core regulator of Central Nervous System (CNS) aging and neurodegeneration. In the brain, it has mostly been studied in neurons, where the delivery of toxic molecules and organelles to the lysosome by autophagy is crucial for neuronal health and survival. However, we propose that the (dys)regulation of autophagy in microglia also affects innate immune functions such as phagocytosis and inflammation, which in turn contribute to the pathophysiology of aging and neurodegenerative diseases. Herein, we first describe the basic concepts of autophagy and its regulation, discuss key aspects for its accurate monitoring at the experimental level, and summarize the evidence linking autophagy impairment to CNS senescence and disease. We focus on acute, chronic, and autoimmunity-mediated neurodegeneration, including ischemia/stroke, Alzheimer’s, Parkinson’s, and Huntington’s diseases, and multiple sclerosis. Next, we describe the actual and potential impact of autophagy on microglial phagocytic and inflammatory function. Thus, we provide evidence of how autophagy may affect microglial phagocytosis of apoptotic cells, amyloid-β, synaptic material, and myelin debris, and regulate the progression of age-associated neurodegenerative diseases. We also discuss data linking autophagy to the regulation of the microglial inflammatory phenotype, which is known to contribute to age-related brain dysfunction. Overall, we update the current knowledge of autophagy and microglia, and highlight as yet unexplored mechanisms whereby autophagy in microglia may contribute to CNS disease and senescence. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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Open AccessReview Microglial Function across the Spectrum of Age and Gender
Int. J. Mol. Sci. 2017, 18(3), 561; doi:10.3390/ijms18030561
Received: 1 February 2017 / Revised: 26 February 2017 / Accepted: 1 March 2017 / Published: 4 March 2017
PDF Full-text (929 KB) | HTML Full-text | XML Full-text
Abstract
Microglia constitute the resident immunocompetent cells of the central nervous system. Although much work has focused on their ability to mount an inflammatory response in reaction to pathology, recent studies have delved into their role in maintaining homeostasis in the healthy brain. It
[...] Read more.
Microglia constitute the resident immunocompetent cells of the central nervous system. Although much work has focused on their ability to mount an inflammatory response in reaction to pathology, recent studies have delved into their role in maintaining homeostasis in the healthy brain. It is important to note that the function of these cells is more complex than originally conceived, as there is increasing evidence that microglial responses can vary greatly among individuals. Here, this review will describe the changing behavior of microglia from development and birth through to the aged brain. Further, it is not only age that impacts the state of the neuroimmune milieu, as microglia have been shown to play a central role in the sexual differentiation of the brain. Finally, this review will discuss the implications this has for the differences in the incidence of neurodegenerative disorders between males and females, and between the young and old. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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Open AccessReview Complex Roles of Microglial Cells in Ischemic Stroke Pathobiology: New Insights and Future Directions
Int. J. Mol. Sci. 2017, 18(3), 496; doi:10.3390/ijms18030496
Received: 9 January 2017 / Revised: 21 February 2017 / Accepted: 22 February 2017 / Published: 25 February 2017
PDF Full-text (530 KB) | HTML Full-text | XML Full-text
Abstract
Ischemic stroke constitutes the major cause of death and disability in the industrialized world. The interest in microglia arose from the evidence outlining the role of neuroinflammation in ischemic stroke pathobiology. Microglia constitute the powerhouse of innate immunity in the brain. Microglial cells
[...] Read more.
Ischemic stroke constitutes the major cause of death and disability in the industrialized world. The interest in microglia arose from the evidence outlining the role of neuroinflammation in ischemic stroke pathobiology. Microglia constitute the powerhouse of innate immunity in the brain. Microglial cells are highly ramified, and use these ramifications as sentinels to detect changes in brain homeostasis. Once a danger signal is recognized, cells become activated and mount specialized responses that range from eliminating cell debris to secreting inflammatory signals and trophic factors. Originally, it was suggested that microglia play essentially a detrimental role in ischemic stroke. However, recent reports are providing evidence that the role of these cells is more complex than what was originally thought. Although these cells play detrimental role in the acute phase, they are required for tissue regeneration in the post-acute phases. This complex role of microglia in ischemic stroke pathobiology constitutes a major challenge for the development of efficient immunomodulatory therapies. This review aims at providing an overview regarding the role of resident microglia and peripherally recruited macrophages in ischemic pathobiology. Furthermore, the review will highlight future directions towards the development of novel fine-tuning immunomodulatory therapeutic interventions. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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Open AccessReview The Diverse Roles of Microglia in the Neurodegenerative Aspects of Central Nervous System (CNS) Autoimmunity
Int. J. Mol. Sci. 2017, 18(3), 504; doi:10.3390/ijms18030504
Received: 19 January 2017 / Revised: 21 February 2017 / Accepted: 21 February 2017 / Published: 25 February 2017
PDF Full-text (4097 KB) | HTML Full-text | XML Full-text
Abstract
Autoimmune diseases of the central nervous system (CNS) involve inflammatory components and result in neurodegenerative processes. Microglia, the resident macrophages of the CNS, are the first responders after insults to the CNS and comprise a major link between the inflammation and neurodegeneration. Here,
[...] Read more.
Autoimmune diseases of the central nervous system (CNS) involve inflammatory components and result in neurodegenerative processes. Microglia, the resident macrophages of the CNS, are the first responders after insults to the CNS and comprise a major link between the inflammation and neurodegeneration. Here, we will focus on the roles of microglia in two autoimmune diseases: the prevalent condition of multiple sclerosis (MS) and the much rarer Rasmussen’s encephalitis (RE). Although there is an abundance of evidence that microglia actively contribute to neuronal damage in pathological states such as MS and RE, there is also evidence of important reparative functions. As current research supports a more complex and diverse array of functions and phenotypes that microglia can assume, it is an especially interesting time to examine what is known about both the damaging and restorative roles that microglia can play in the inflammatory CNS setting. We will also discuss the pharmacological approaches to modulating microglia towards a more neuroprotective state. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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