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Microglia in Aging and Neurodegenerative Disease
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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: closed (30 September 2017) | Viewed by 170877

Special Issue Editors

Dr. Jillian Nissen

E-Mail Website
Co-Guest Editor
Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA
Interests: microglia; autoimmune disease; gender differences; neurodegeneration
Prof. Styliani-Anna (Stella) E. Tsirka

E-Mail Website
Guest Editor
Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA
Interests: microglia; neuroimmune interactions; models of disease; neurodegeneration; innate immunity; crosstalk
Special Issues, Collections and Topics in MDPI journals

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

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Keywords

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

Published Papers (16 papers)

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Research

Jump to: Review

5987 KiB  
Article
Abscopal Activation of Microglia in Embryonic Fish Brain Following Targeted Irradiation with Heavy-Ion Microbeam
by Takako Yasuda, Miyuki Kamahori, Kento Nagata, Tomomi Watanabe-Asaka, Michiyo Suzuki, Tomoo Funayama, Hiroshi Mitani and Shoji Oda
Int. J. Mol. Sci. 2017, 18(7), 1428; https://doi.org/10.3390/ijms18071428 - 04 Jul 2017
Cited by 15 | Viewed by 6850
Abstract
Microglia remove apoptotic cells by phagocytosis when the central nervous system is injured in vertebrates. Ionizing irradiation (IR) induces apoptosis and microglial activation in embryonic midbrain of medaka (Oryzias latipes), where apolipoprotein E (ApoE) is upregulated in the later phase of [...] Read more.
Microglia remove apoptotic cells by phagocytosis when the central nervous system is injured in vertebrates. Ionizing irradiation (IR) induces apoptosis and microglial activation in embryonic midbrain of medaka (Oryzias latipes), where apolipoprotein E (ApoE) is upregulated in the later phase of activation of microglia In this study, we found that another microglial marker, l-plastin (lymphocyte cytosolic protein 1), was upregulated at the initial phase of the IR-induced phagocytosis when activated microglia changed their morphology and increased motility to migrate. We further conducted targeted irradiation to the embryonic midbrain using a collimated microbeam of carbon ions (250 μm diameter) and found that the l-plastin upregulation was induced only in the microglia located in the irradiated area. Then, the activated microglia might migrate outside of the irradiated area and spread through over the embryonic brain, expressing ApoE and with activated morphology, for longer than 3 days after the irradiation. These findings suggest that l-plastin and ApoE can be the biomarkers of the activated microglia in the initial and later phase, respectively, in the medaka embryonic brain and that the abscopal and persisted activation of microglia by IR irradiation could be a cause of the abscopal and/or adverse effects following irradiation. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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Article
Annexin-1 Mediates Microglial Activation and Migration via the CK2 Pathway during Oxygen–Glucose Deprivation/Reperfusion
by Shuangxi Liu, Yan Gao, Xiaoli Yu, Baoming Zhao, Lu Liu, Yin Zhao, Zhenzhao Luo and Jing Shi
Int. J. Mol. Sci. 2016, 17(10), 1770; https://doi.org/10.3390/ijms17101770 - 22 Oct 2016
Cited by 135 | Viewed by 6945
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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27 pages, 2924 KiB  
Review
Microglia and Aging: The Role of the TREM2–DAP12 and CX3CL1-CX3CR1 Axes
by Carmen Mecca, Ileana Giambanco, Rosario Donato and Cataldo Arcuri
Int. J. Mol. Sci. 2018, 19(1), 318; https://doi.org/10.3390/ijms19010318 - 22 Jan 2018
Cited by 155 | Viewed by 17217
Abstract
Depending on the species, microglial cells represent 5–20% of glial cells in the adult brain. As the innate immune effector of the brain, microglia are involved in several functions: regulation of inflammation, synaptic connectivity, programmed cell death, wiring and circuitry formation, phagocytosis of [...] Read more.
Depending on the species, microglial cells represent 5–20% of glial cells in the adult brain. As the innate immune effector of the brain, microglia are involved in several functions: regulation of inflammation, synaptic connectivity, programmed cell death, wiring and circuitry formation, phagocytosis of cell debris, and synaptic pruning and sculpting of postnatal neural circuits. Moreover, microglia contribute to some neurodevelopmental disorders such as Nasu-Hakola disease (NHD), and to aged-associated neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and others. There is evidence that human and rodent microglia may become senescent. This event determines alterations in the microglia activation status, associated with a chronic inflammation phenotype and with the loss of neuroprotective functions that lead to a greater susceptibility to the neurodegenerative diseases of aging. In the central nervous system (CNS), Triggering Receptor Expressed on Myeloid Cells 2-DNAX activation protein 12 (TREM2-DAP12) is a signaling complex expressed exclusively in microglia. As a microglial surface receptor, TREM2 interacts with DAP12 to initiate signal transduction pathways that promote microglial cell activation, phagocytosis, and microglial cell survival. Defective TREM2-DAP12 functions play a central role in the pathogenesis of several diseases. The CX3CL1 (fractalkine)-CX3CR1 signaling represents the most important communication channel between neurons and microglia. The expression of CX3CL1 in neurons and of its receptor CX3CR1 in microglia determines a specific interaction, playing fundamental roles in the regulation of the maturation and function of these cells. Here, we review the role of the TREM2-DAP12 and CX3CL1-CX3CR1 axes in aged microglia and the involvement of these pathways in physiological CNS aging and in age-associated neurodegenerative diseases. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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10 pages, 919 KiB  
Review
Neuroimmune-Driven Neuropathic Pain Establishment: A Focus on Gender Differences
by Vincenzo Coraggio, Francesca Guida, Serena Boccella, Mariantonietta Scafuro, Salvatore Paino, Domenico Romano, Sabatino Maione and Livio Luongo
Int. J. Mol. Sci. 2018, 19(1), 281; https://doi.org/10.3390/ijms19010281 - 17 Jan 2018
Cited by 42 | Viewed by 5593
Abstract
The role of neuroinflammatory cells in the establishment of neuropathic pain has been investigated in depth in the last few years. In particular, microglia have been shown to be key players in the induction of tactile allodynia, as they release proinflammatory molecules that, [...] Read more.
The role of neuroinflammatory cells in the establishment of neuropathic pain has been investigated in depth in the last few years. In particular, microglia have been shown to be key players in the induction of tactile allodynia, as they release proinflammatory molecules that, in turn, sensitize nociceptive neurons within the spinal cord. However, the role of peripheral immune cells such as macrophages, infiltrating monocytes, mast cells, and T-cells has been highlighted in the last few studies, even though the data are still conflicting and need to be clarified. Intriguingly, the central (microglia) and peripheral (T-cell)-adaptive immune cells that orchestrate maladaptive process-driven neuropathic pain seem to be involved in a gender-dependent manner. In this review, we highlight the role of the microglia and peripheral immune cells in chronic degenerative disease associated with neuro-immune-inflammatory processes. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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31 pages, 1636 KiB  
Review
The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration
by Christine Altmann and Mirko H. H. Schmidt
Int. J. Mol. Sci. 2018, 19(1), 110; https://doi.org/10.3390/ijms19010110 - 01 Jan 2018
Cited by 262 | Viewed by 15546
Abstract
Diabetic retinopathy is a common complication of diabetes mellitus, which appears in one third of all diabetic patients and is a prominent cause of vision loss. First discovered as a microvascular disease, intensive research in the field identified inflammation and neurodegeneration to be [...] Read more.
Diabetic retinopathy is a common complication of diabetes mellitus, which appears in one third of all diabetic patients and is a prominent cause of vision loss. First discovered as a microvascular disease, intensive research in the field identified inflammation and neurodegeneration to be part of diabetic retinopathy. Microglia, the resident monocytes of the retina, are activated due to a complex interplay between the different cell types of the retina and diverse pathological pathways. The trigger for developing diabetic retinopathy is diabetes-induced hyperglycemia, accompanied by leukostasis and vascular leakages. Transcriptional changes in activated microglia, mediated via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and extracellular signal–regulated kinase (ERK) signaling pathways, results in release of various pro-inflammatory mediators, including cytokines, chemokines, caspases and glutamate. Activated microglia additionally increased proliferation and migration. Among other consequences, these changes in microglia severely affected retinal neurons, causing increased apoptosis and subsequent thinning of the nerve fiber layer, resulting in visual loss. New potential therapeutics need to interfere with these diabetic complications even before changes in the retina are diagnosed, to prevent neuronal apoptosis and blindness in patients. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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2005 KiB  
Review
In Vivo Imaging of Microglial Calcium Signaling in Brain Inflammation and Injury
by Petr Tvrdik and M. Yashar S. Kalani
Int. J. Mol. Sci. 2017, 18(11), 2366; https://doi.org/10.3390/ijms18112366 - 08 Nov 2017
Cited by 41 | Viewed by 8730
Abstract
Microglia, the innate immune sentinels of the central nervous system, are the most dynamic cells in the brain parenchyma. They are the first responders to insult and mediate neuroinflammation. Following cellular damage, microglia extend their processes towards the lesion, modify their morphology, release [...] Read more.
Microglia, the innate immune sentinels of the central nervous system, are the most dynamic cells in the brain parenchyma. They are the first responders to insult and mediate neuroinflammation. Following cellular damage, microglia extend their processes towards the lesion, modify their morphology, release cytokines and other mediators, and eventually migrate towards the damaged area and remove cellular debris by phagocytosis. Intracellular Ca2+ signaling plays important roles in many of these functions. However, Ca2+ in microglia has not been systematically studied in vivo. Here we review recent findings using genetically encoded Ca2+ indicators and two-photon imaging, which have enabled new insights into Ca2+ dynamics and signaling pathways in large populations of microglia in vivo. These new approaches will help to evaluate pre-clinical interventions and immunomodulation for pathological brain conditions such as stroke and neurodegenerative diseases. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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1630 KiB  
Review
Microglia and Monocytes/Macrophages Polarization Reveal Novel Therapeutic Mechanism against Stroke
by Masato Kanazawa, Itaru Ninomiya, Masahiro Hatakeyama, Tetsuya Takahashi and Takayoshi Shimohata
Int. J. Mol. Sci. 2017, 18(10), 2135; https://doi.org/10.3390/ijms18102135 - 13 Oct 2017
Cited by 294 | Viewed by 15017
Abstract
Stroke is a leading cause of morbidity and mortality worldwide, and consists of two types, ischemic and hemorrhagic. Currently, there is no effective treatment to increase the survival rate or improve the quality of life after ischemic and hemorrhagic stroke in the subacute [...] Read more.
Stroke is a leading cause of morbidity and mortality worldwide, and consists of two types, ischemic and hemorrhagic. Currently, there is no effective treatment to increase the survival rate or improve the quality of life after ischemic and hemorrhagic stroke in the subacute to chronic phases. Therefore, it is necessary to establish therapeutic strategies to facilitate functional recovery in patients with stroke during both phases. Cell-based therapies, using microglia and monocytes/macrophages preconditioned by optimal stimuli and/or any therapies targeting these cells, might be an ideal therapeutic strategy for managing stroke. Microglia and monocytes/macrophages polarize to the classic pro-inflammatory type (M1-like) or alternative protective type (M2-like) by optimal condition. Cell-based therapies using M2-like microglia and monocytes/macrophages might be protective therapeutic strategies against stroke for three reasons. First, M2-like microglia and monocytes/monocytes secrete protective remodeling factors, thus prompting neuronal network recovery via tissue (including neuronal) and vascular remodeling. Second, these cells could migrate to the injured hemisphere through the blood–brain barrier or choroid–plexus. Third, these cells could mitigate the extent of inflammation-induced injuries by suitable timing of therapeutic intervention. Although future translational studies are required, M2-like microglia and monocytes/macrophages therapies are attractive for managing stroke based on their protective functions. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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2600 KiB  
Review
Neuron–Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region
by Mohammad Zakir Hossain, Shumpei Unno, Hiroshi Ando, Yuji Masuda and Junichi Kitagawa
Int. J. Mol. Sci. 2017, 18(10), 2051; https://doi.org/10.3390/ijms18102051 - 26 Sep 2017
Cited by 47 | Viewed by 9432
Abstract
Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to [...] Read more.
Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate–glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron–glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP. Full article
(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)
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1780 KiB  
Review
Molecular Imaging of Neuroinflammation in Neurodegenerative Dementias: The Role of In Vivo PET Imaging
by Chiara Cerami, Leonardo Iaccarino and Daniela Perani
Int. J. Mol. Sci. 2017, 18(5), 993; https://doi.org/10.3390/ijms18050993 - 05 May 2017
Cited by 59 | Viewed by 10861
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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308 KiB  
Review
Molecular Targets for PET Imaging of Activated Microglia: The Current Situation and Future Expectations
by Claire Tronel, Bérenger Largeau, Maria Joao Santiago Ribeiro, Denis Guilloteau, Anne-Claire Dupont and Nicolas Arlicot
Int. J. Mol. Sci. 2017, 18(4), 802; https://doi.org/10.3390/ijms18040802 - 11 Apr 2017
Cited by 101 | Viewed by 7506
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)
524 KiB  
Review
Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases
by Anne-Claire Dupont, Bérenger Largeau, Maria Joao Santiago Ribeiro, Denis Guilloteau, Claire Tronel and Nicolas Arlicot
Int. J. Mol. Sci. 2017, 18(4), 785; https://doi.org/10.3390/ijms18040785 - 07 Apr 2017
Cited by 128 | Viewed by 10206
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)
3471 KiB  
Review
Old Maids: Aging and Its Impact on Microglia Function
by Edward C. Koellhoffer, Louise D. McCullough and Rodney M. Ritzel
Int. J. Mol. Sci. 2017, 18(4), 769; https://doi.org/10.3390/ijms18040769 - 05 Apr 2017
Cited by 147 | Viewed by 11608
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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1233 KiB  
Review
Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging
by Ainhoa Plaza-Zabala, Virginia Sierra-Torre and Amanda Sierra
Int. J. Mol. Sci. 2017, 18(3), 598; https://doi.org/10.3390/ijms18030598 - 09 Mar 2017
Cited by 235 | Viewed by 20035
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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929 KiB  
Review
Microglial Function across the Spectrum of Age and Gender
by Jillian C. Nissen
Int. J. Mol. Sci. 2017, 18(3), 561; https://doi.org/10.3390/ijms18030561 - 04 Mar 2017
Cited by 55 | Viewed by 8617
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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4097 KiB  
Review
The Diverse Roles of Microglia in the Neurodegenerative Aspects of Central Nervous System (CNS) Autoimmunity
by Kaitlyn K. Thompson and Stella E. Tsirka
Int. J. Mol. Sci. 2017, 18(3), 504; https://doi.org/10.3390/ijms18030504 - 25 Feb 2017
Cited by 64 | Viewed by 7669
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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530 KiB  
Review
Complex Roles of Microglial Cells in Ischemic Stroke Pathobiology: New Insights and Future Directions
by Revathy Guruswamy and Ayman ElAli
Int. J. Mol. Sci. 2017, 18(3), 496; https://doi.org/10.3390/ijms18030496 - 25 Feb 2017
Cited by 113 | Viewed by 7568
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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