Editorial

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5 pages, 425 KiB

Open AccessEditorial

Glial–Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention

by Agata Adamczyk

Int. J. Mol. Sci. 2023, 24(7), 6274; https://doi.org/10.3390/ijms24076274 - 27 Mar 2023

Cited by 3 | Viewed by 2057

Abstract

Neurons have long been central to the study of cellular networks in the nervous system [...] Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention 2.0)

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Research

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22 pages, 30325 KiB

Open AccessArticle

The Role of ATF3 in Neuronal Differentiation and Development of Neuronal Networks in Opossum Postnatal Cortical Cultures

by Antonela Petrović, Jelena Ban, Matea Ivaničić, Ivana Tomljanović and Miranda Mladinic

Int. J. Mol. Sci. 2022, 23(9), 4964; https://doi.org/10.3390/ijms23094964 - 29 Apr 2022

Cited by 8 | Viewed by 2237

Abstract

Activating transcription factor 3 (ATF3), a member of the ATF/cAMP response element-binding (CREB) family, is upregulated by various intracellular and extracellular signals such as injury and signals related to cell proliferation. ATF3 also belongs to the regeneration-associated genes (RAG) group of transcription factors. [...] Read more.

Activating transcription factor 3 (ATF3), a member of the ATF/cAMP response element-binding (CREB) family, is upregulated by various intracellular and extracellular signals such as injury and signals related to cell proliferation. ATF3 also belongs to the regeneration-associated genes (RAG) group of transcription factors. RAG and ATF/CREB transcription factors that play an important role in embryonic neuronal development and PNS regeneration may also be involved in postnatal neuronal differentiation and development, as well as in the regeneration of the injured CNS. Here we investigated the effect of ATF3 in differentiation, neural outgrowth, network formation, and regeneration after injury using postnatal dissociated cortical neurons derived from neonatal opossums (Monodelphis domestica). Our results show that RAG and ATF genes are differentially expressed in early differentiated neurons versus undifferentiated neurospheres and that many members of those families, ATF3 in particular, are upregulated in cortical cultures obtained from younger animals that have the ability to fully functionally regenerate spinal cord after injury. In addition, we observed different intracellular localization of ATF3 that shifts from nuclear (in neuronal progenitors) to cytoplasmic (in more mature neurons) during neuronal differentiation. The ATF3 inhibition, pharmacological or by specific antibody, reduced the neurite outgrowth and differentiation and caused increased cell death in early differentiating cortical neuronal cultures, suggesting the importance of ATF3 in the CNS development of neonatal opossums. Finally, we investigated the regeneration capacity of primary cortical cultures after mechanical injury using the scratch assay. Remarkably, neonatal opossum-derived cultures retain their capacity to regenerate for up to 1 month in vitro. Inhibition of ATF3 correlates with reduced neurite outgrowth and regeneration after injury. These results indicate that ATF3, and possibly other members of RAG and ATF/CREB family of transcription factors, have an important role both during cortical postnatal development and in response after injury. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention 2.0)

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14 pages, 4776 KiB

Open AccessArticle

Microglial Activation Damages Dopaminergic Neurons through MMP-2/-9-Mediated Increase of Blood-Brain Barrier Permeability in a Parkinson’s Disease Mouse Model

by Zhengzheng Ruan, Dongdong Zhang, Ruixue Huang, Wei Sun, Liyan Hou, Jie Zhao and Qingshan Wang

Int. J. Mol. Sci. 2022, 23(5), 2793; https://doi.org/10.3390/ijms23052793 - 03 Mar 2022

Cited by 26 | Viewed by 2683

Abstract

Chronic neuroinflammation has been considered to be involved in the progressive dopaminergic neurodegeneration in Parkinson’s disease (PD). However, the mechanisms remain unknown. Accumulating evidence indicated a key role of the blood–brain barrier (BBB) dysfunction in neurological disorders. This study is designed to elucidate [...] Read more.

Chronic neuroinflammation has been considered to be involved in the progressive dopaminergic neurodegeneration in Parkinson’s disease (PD). However, the mechanisms remain unknown. Accumulating evidence indicated a key role of the blood–brain barrier (BBB) dysfunction in neurological disorders. This study is designed to elucidate whether chronic neuroinflammation damages dopaminergic neurons through BBB dysfunction by using a rotenone-induced mouse PD model. Results showed that rotenone dose-dependently induced nigral dopaminergic neurodegeneration, which was associated with increased Evans blue content and fibrinogen accumulation as well as reduced expressions of zonula occludens-1 (ZO-1), claudin-5 and occludin, three tight junction proteins for maintaining BBB permeability, in mice, indicating BBB disruption. Rotenone also induced nigral microglial activation. Depletion of microglia or inhibition of microglial activation by PLX3397 or minocycline, respectively, greatly attenuated BBB dysfunction in rotenone-lesioned mice. Mechanistic inquiry revealed that microglia-mediated activation of matrix metalloproteinases-2 and 9 (MMP-2/-9) contributed to rotenone-induced BBB disruption and dopaminergic neurodegeneration. Rotenone-induced activation of MMP-2/-9 was significantly attenuated by microglial depletion and inactivation. Furthermore, inhibition of MMP-2/-9 by a wide-range inhibitor, SB-3CT, abrogated elevation of BBB permeability and simultaneously increased tight junctions expression. Finally, we found that microglial depletion and inactivation as well as inhibition of MMP-2/-9 significantly ameliorated rotenone-elicited nigrostriatal dopaminergic neurodegeneration and motor dysfunction in mice. Altogether, our findings suggested that microglial MMP-2/-9 activation-mediated BBB dysfunction contributed to dopaminergic neurodegeneration in rotenone-induced mouse PD model, providing a novel view for the mechanisms of Parkinsonism. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention 2.0)

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20 pages, 4674 KiB

Open AccessArticle

Protection of Cholinergic Neurons against Zinc Toxicity by Glial Cells in Thiamine-Deficient Media

by Sylwia Gul-Hinc, Anna Michno, Marlena Zyśk, Andrzej Szutowicz, Agnieszka Jankowska-Kulawy and Anna Ronowska

Int. J. Mol. Sci. 2021, 22(24), 13337; https://doi.org/10.3390/ijms222413337 - 11 Dec 2021

Cited by 5 | Viewed by 2071

Abstract

Brain pathologies evoked by thiamine deficiency can be aggravated by mild zinc excess. Cholinergic neurons are the most susceptible to such cytotoxic signals. Sub-toxic zinc excess aggravates the injury of neuronal SN56 cholinergic cells under mild thiamine deficiency. The excessive cell loss is [...] Read more.

Brain pathologies evoked by thiamine deficiency can be aggravated by mild zinc excess. Cholinergic neurons are the most susceptible to such cytotoxic signals. Sub-toxic zinc excess aggravates the injury of neuronal SN56 cholinergic cells under mild thiamine deficiency. The excessive cell loss is caused by Zn interference with acetyl-CoA metabolism. The aim of this work was to investigate whether and how astroglial C6 cells alleviated the neurotoxicity of Zn to cultured SN56 cells in thiamine-deficient media. Low Zn concentrations did not affect astroglial C6 and primary glial cell viability in thiamine-deficient conditions. Additionally, parameters of energy metabolism were not significantly changed. Amprolium (a competitive inhibitor of thiamine uptake) augmented thiamine pyrophosphate deficits in cells, while co-treatment with Zn enhanced the toxic effect on acetyl-CoA metabolism. SN56 cholinergic neuronal cells were more susceptible to these combined insults than C6 and primary glial cells, which affected pyruvate dehydrogenase activity and the acetyl-CoA level. A co-culture of SN56 neurons with astroglial cells in thiamine-deficient medium eliminated Zn-evoked neuronal loss. These data indicate that astroglial cells protect neurons against Zn and thiamine deficiency neurotoxicity by preserving the acetyl-CoA level. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention 2.0)

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20 pages, 9895 KiB

Open AccessArticle

Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca²⁺ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders

by Grzegorz A. Czapski, Yuhai Zhao, Walter J. Lukiw and Joanna B. Strosznajder

Int. J. Mol. Sci. 2020, 21(21), 7838; https://doi.org/10.3390/ijms21217838 - 22 Oct 2020

Cited by 11 | Viewed by 2887

Abstract

Acute systemic inflammatory response (SIR) triggers an alteration in the transcription of brain genes related to neuroinflammation, oxidative stress and cells death. These changes are also characteristic for Alzheimer’s disease (AD) neuropathology. Our aim was to evaluate gene expression patterns in the mouse [...] Read more.

Acute systemic inflammatory response (SIR) triggers an alteration in the transcription of brain genes related to neuroinflammation, oxidative stress and cells death. These changes are also characteristic for Alzheimer’s disease (AD) neuropathology. Our aim was to evaluate gene expression patterns in the mouse hippocampus (MH) by using microarray technology 12 and 96 h after SIR evoked by lipopolysaccharide (LPS). The results were compared with microarray analysis of human postmortem hippocampal AD tissues. It was found that 12 h after LPS administration the expression of 231 genes in MH was significantly altered (FC > 2.0); however, after 96 h only the S100a8 gene encoding calgranulin A was activated (FC = 2.9). Gene ontology enrichment analysis demonstrated the alteration of gene expression related mostly to the immune-response including the gene Lcn2 for Lipocalin 2 (FC = 237.8), involved in glia neurotoxicity. The expression of genes coding proteins involved in epigenetic regulation, histone deacetylases (Hdac4,5,8,9,11) and bromo- and extraterminal domain protein Brd3 were downregulated; however, Brd2 was found to be upregulated. Remarkably, the significant increase in expression of Lcn2, S100a8, S100a9 and also Saa3 and Ch25h, was found in AD brains suggesting that early changes of immune-response genes evoked by mild SIR could be crucial in AD pathogenesis. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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17 pages, 6300 KiB

Open AccessArticle

Neuroimmune Response in Natural Preclinical Scrapie after Dexamethasone Treatment

by Isabel M. Guijarro, Moisés Garcés, Belén Marín, Alicia Otero, Tomás Barrio, Juan J. Badiola and Marta Monzón

Int. J. Mol. Sci. 2020, 21(16), 5779; https://doi.org/10.3390/ijms21165779 - 12 Aug 2020

Cited by 4 | Viewed by 2152

Abstract

A recently published report on chronic dexamethasone treatment for natural scrapie supported the hypothesis of the potential failure of astroglia in the advanced stage of disease. Herein, we aimed to extend the aforementioned study on the effect of this anti-inflammatory therapy to the [...] Read more.

A recently published report on chronic dexamethasone treatment for natural scrapie supported the hypothesis of the potential failure of astroglia in the advanced stage of disease. Herein, we aimed to extend the aforementioned study on the effect of this anti-inflammatory therapy to the initial phase of scrapie, with the aim of elucidating the natural neuroinflammatory process occurring in this neurodegenerative disorder. The administration of this glucocorticoid resulted in an outstanding reduction in vacuolation and aberrant protein deposition (nearly null), and an increase in glial activation. Furthermore, evident suppression of IL-1R and IL-6 and the exacerbation of IL-1α, IL-2R, IL-10R and IFNγR were also demonstrated. Consequently, the early stage of the disease is characterized by an intact neuroglial response similar to that of healthy individuals attempting to re-establish homeostasis. A complex network of neuroinflammatory markers is involved from the very early stages of this prion disease, which probably becomes impaired in the more advanced stages. The in vivo animal model used herein provides essential observations on the pathogenesis of natural scrapie, as well as the possibility of establishing neuroglia as potential target cells for anti-inflammatory therapy. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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29 pages, 8514 KiB

Open AccessArticle

Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring

by Magdalena Cieślik, Magdalena Gąssowska-Dobrowolska, Henryk Jęśko, Grzegorz A. Czapski, Anna Wilkaniec, Aleksandra Zawadzka, Agnieszka Dominiak, Rafał Polowy, Robert K. Filipkowski, Paweł M. Boguszewski, Magdalena Gewartowska, Małgorzata Frontczak-Baniewicz, Grace Y. Sun, David Q. Beversdorf and Agata Adamczyk

Int. J. Mol. Sci. 2020, 21(11), 4097; https://doi.org/10.3390/ijms21114097 - 08 Jun 2020

Cited by 36 | Viewed by 5419

Abstract

Maternal immune activation (MIA), induced by infection during pregnancy, is an important risk factor for neuro-developmental disorders, such as autism. Abnormal maternal cytokine signaling may affect fetal brain development and contribute to neurobiological and behavioral changes in the offspring. Here, we examined the [...] Read more.

Maternal immune activation (MIA), induced by infection during pregnancy, is an important risk factor for neuro-developmental disorders, such as autism. Abnormal maternal cytokine signaling may affect fetal brain development and contribute to neurobiological and behavioral changes in the offspring. Here, we examined the effect of lipopolysaccharide-induced MIA on neuro-inflammatory changes, as well as synaptic morphology and key synaptic protein level in cerebral cortex of adolescent male rat offspring. Adolescent MIA offspring showed elevated blood cytokine levels, microglial activation, increased pro-inflammatory cytokines expression and increased oxidative stress in the cerebral cortex. Moreover, pathological changes in synaptic ultrastructure of MIA offspring was detected, along with presynaptic protein deficits and down-regulation of postsynaptic scaffolding proteins. Consequently, ability to unveil MIA-induced long-term alterations in synapses structure and protein level may have consequences on postnatal behavioral changes, associated with, and predisposed to, the development of neuropsychiatric disorders. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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33 pages, 7463 KiB

Open AccessArticle

Prenatal Exposure to Valproic Acid Affects Microglia and Synaptic Ultrastructure in a Brain-Region-Specific Manner in Young-Adult Male Rats: Relevance to Autism Spectrum Disorders

by Magdalena Gąssowska-Dobrowolska, Magdalena Cieślik, Grzegorz Arkadiusz Czapski, Henryk Jęśko, Małgorzata Frontczak-Baniewicz, Magdalena Gewartowska, Agnieszka Dominiak, Rafał Polowy, Robert Kuba Filipkowski, Lidia Babiec and Agata Adamczyk

Int. J. Mol. Sci. 2020, 21(10), 3576; https://doi.org/10.3390/ijms21103576 - 18 May 2020

Cited by 37 | Viewed by 5180

Abstract

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions categorized as synaptopathies. Environmental risk factors contribute to ASD aetiology. In particular, prenatal exposure to the anti-epileptic drug valproic acid (VPA) may increase the risk of autism. In the present study, we [...] Read more.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions categorized as synaptopathies. Environmental risk factors contribute to ASD aetiology. In particular, prenatal exposure to the anti-epileptic drug valproic acid (VPA) may increase the risk of autism. In the present study, we investigated the effect of prenatal exposure to VPA on the synaptic morphology and expression of key synaptic proteins in the hippocampus and cerebral cortex of young-adult male offspring. To characterize the VPA-induced autism model, behavioural outcomes, microglia-related neuroinflammation, and oxidative stress were analysed. Our data showed that prenatal exposure to VPA impaired communication in neonatal rats, reduced their exploratory activity, and led to anxiety-like and repetitive behaviours in the young-adult animals. VPA-induced pathological alterations in the ultrastructures of synapses accompanied by deregulation of key pre- and postsynaptic structural and functional proteins. Moreover, VPA exposure altered the redox status and expression of proinflammatory genes in a brain region-specific manner. The disruption of synaptic structure and plasticity may be the primary insult responsible for autism-related behaviour in the offspring. The vulnerability of specific synaptic proteins to the epigenetic effects of VPA may highlight the potential mechanisms by which prenatal VPA exposure generates behavioural changes. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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12 pages, 3219 KiB

Open AccessArticle

Homeostasis Imbalance of Microglia and Astrocytes Leads to Alteration in the Metabolites of the Kynurenine Pathway in LPS-Induced Depressive-Like Mice

by Xue Tao, Mingzhu Yan, Lisha Wang, Yunfeng Zhou, Zhi Wang, Tianji Xia, Xinmin Liu, Ruile Pan and Qi Chang

Int. J. Mol. Sci. 2020, 21(4), 1460; https://doi.org/10.3390/ijms21041460 - 21 Feb 2020

Cited by 31 | Viewed by 4105

Abstract

In the pathology-oriented study of depression, inflammation hypothesis has received increasing attention for recent years. To mimic the depressive state caused by inflammation, rodents injected intraperitoneally with lipopolysaccharide (LPS) are usually used to stimulate an immune response. However, the dose of LPS that [...] Read more.

In the pathology-oriented study of depression, inflammation hypothesis has received increasing attention for recent years. To mimic the depressive state caused by inflammation, rodents injected intraperitoneally with lipopolysaccharide (LPS) are usually used to stimulate an immune response. However, the dose of LPS that causes depressive-like behavior varies widely across many literatures. Previous study has uncovered the non-linearity in the dose-effect relationship for the depressive-like behavior induced by LPS administration, while the reason for this is still unclear. The present study aims to investigate the underlying mechanisms of this non-linear dose-dependent relationship. Four groups of mice were injected intraperitoneally with different doses of LPS (0, 0.32, 0.8, and 2 mg/kg). The tail suspension test was conducted to evaluate the depressive-like behavior within 23–25 h after the LPS administration. The neuroplasticity was assessed by the levels of related proteins, TrkB and PSD-95, and by the quantification of neurons using Nissl staining. The levels of the two metabolites of the kynurenine (KYN) pathway, 3-hydroxykynurenine (3-HK) and kynurenic acid (KYNA), in the brain were analyzed by LC-MS/MS. Activation of microglia and astrocytes in the brain were also determined by immunohistochemistry and western blotting, respectively. The results showed that, compared with the control group, the mice in the 0.8 mg/kg LPS-treated group exhibited a remarkable increase of immobility time in the tail suspension test. The neuroplasticity of mice in the 0.8 mg/kg LPS-treated group was also significantly reduced. The neurotoxic metabolite, 3-HK, was accumulated significantly in the hippocampus of the 0.8 mg/kg LPS-treated mice. Surprisingly, the 2 mg/kg LPS-treated mice did not exhibit a remarkable change of 3-HK but expressed increased KYNA significantly, which is neuroprotective. Furthermore, the activation of microglia and astrocytes, which were recognized as the primary source of 3-HK and KYNA, respectively, corresponded to the content of these two metabolites of the KYN pathway in each group. Consequently, it was speculated that the homeostasis of different glial cells could lead to a non-linear dose-dependent behavior by regulating the KYN pathway in the LPS-induced depressive-like mice. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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Review

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21 pages, 1299 KiB

Open AccessReview

Glia-Neurotrophic Factor Relationships: Possible Role in Pathobiology of Neuroinflammation-Related Brain Disorders

by Ewelina Palasz, Anna Wilkaniec, Luiza Stanaszek, Anna Andrzejewska and Agata Adamczyk

Int. J. Mol. Sci. 2023, 24(7), 6321; https://doi.org/10.3390/ijms24076321 - 28 Mar 2023

Cited by 3 | Viewed by 2151

Abstract

Neurotrophic factors (NTFs) play an important role in maintaining homeostasis of the central nervous system (CNS) by regulating the survival, differentiation, maturation, and development of neurons and by participating in the regeneration of damaged tissues. Disturbances in the level and functioning of NTFs [...] Read more.

Neurotrophic factors (NTFs) play an important role in maintaining homeostasis of the central nervous system (CNS) by regulating the survival, differentiation, maturation, and development of neurons and by participating in the regeneration of damaged tissues. Disturbances in the level and functioning of NTFs can lead to many diseases of the nervous system, including degenerative diseases, mental diseases, and neurodevelopmental disorders. Each CNS disease is characterized by a unique pathomechanism, however, the involvement of certain processes in its etiology is common, such as neuroinflammation, dysregulation of NTFs levels, or mitochondrial dysfunction. It has been shown that NTFs can control the activation of glial cells by directing them toward a neuroprotective and anti-inflammatory phenotype and activating signaling pathways responsible for neuronal survival. In this review, our goal is to outline the current state of knowledge about the processes affected by NTFs, the crosstalk between NTFs, mitochondria, and the nervous and immune systems, leading to the inhibition of neuroinflammation and oxidative stress, and thus the inhibition of the development and progression of CNS disorders. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention 2.0)

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43 pages, 26242 KiB

Open AccessReview

Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain

by Agnieszka Jankowska-Kulawy, Joanna Klimaszewska-Łata, Sylwia Gul-Hinc, Anna Ronowska and Andrzej Szutowicz

Int. J. Mol. Sci. 2022, 23(17), 10073; https://doi.org/10.3390/ijms231710073 - 03 Sep 2022

Cited by 15 | Viewed by 5602

Abstract

The human brain is characterised by the most diverse morphological, metabolic and functional structure among all body tissues. This is due to the existence of diverse neurons secreting various neurotransmitters and mutually modulating their own activity through thousands of pre- and postsynaptic interconnections [...] Read more.

The human brain is characterised by the most diverse morphological, metabolic and functional structure among all body tissues. This is due to the existence of diverse neurons secreting various neurotransmitters and mutually modulating their own activity through thousands of pre- and postsynaptic interconnections in each neuron. Astroglial, microglial and oligodendroglial cells and neurons reciprocally regulate the metabolism of key energy substrates, thereby exerting several neuroprotective, neurotoxic and regulatory effects on neuronal viability and neurotransmitter functions. Maintenance of the pool of mitochondrial acetyl-CoA derived from glycolytic glucose metabolism is a key factor for neuronal survival. Thus, acetyl-CoA is regarded as a direct energy precursor through the TCA cycle and respiratory chain, thereby affecting brain cell viability. It is also used for hundreds of acetylation reactions, including N-acetyl aspartate synthesis in neuronal mitochondria, acetylcholine synthesis in cholinergic neurons, as well as divergent acetylations of several proteins, peptides, histones and low-molecular-weight species in all cellular compartments. Therefore, acetyl-CoA should be considered as the central point of metabolism maintaining equilibrium between anabolic and catabolic pathways in the brain. This review presents data supporting this thesis. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention 2.0)

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21 pages, 3345 KiB

Open AccessReview

Glial-Neuronal Interactions in Pathogenesis and Treatment of Spinal Cord Injury

by Nadezda Lukacova, Alexandra Kisucka, Katarina Kiss Bimbova, Maria Bacova, Maria Ileninova, Tomas Kuruc and Jan Galik

Int. J. Mol. Sci. 2021, 22(24), 13577; https://doi.org/10.3390/ijms222413577 - 17 Dec 2021

Cited by 39 | Viewed by 5788

Abstract

Traumatic spinal cord injury (SCI) elicits an acute inflammatory response which comprises numerous cell populations. It is driven by the immediate response of macrophages and microglia, which triggers activation of genes responsible for the dysregulated microenvironment within the lesion site and in the [...] Read more.

Traumatic spinal cord injury (SCI) elicits an acute inflammatory response which comprises numerous cell populations. It is driven by the immediate response of macrophages and microglia, which triggers activation of genes responsible for the dysregulated microenvironment within the lesion site and in the spinal cord parenchyma immediately adjacent to the lesion. Recently published data indicate that microglia induces astrocyte activation and determines the fate of astrocytes. Conversely, astrocytes have the potency to trigger microglial activation and control their cellular functions. Here we review current information about the release of diverse signaling molecules (pro-inflammatory vs. anti-inflammatory) in individual cell phenotypes (microglia, astrocytes, blood inflammatory cells) in acute and subacute SCI stages, and how they contribute to delayed neuronal death in the surrounding spinal cord tissue which is spared and functional but reactive. In addition, temporal correlation in progressive degeneration of neurons and astrocytes and their functional interactions after SCI are discussed. Finally, the review highlights the time-dependent transformation of reactive microglia and astrocytes into their neuroprotective phenotypes (M2a, M2c and A2) which are crucial for spontaneous post-SCI locomotor recovery. We also provide suggestions on how to modulate the inflammation and discuss key therapeutic approaches leading to better functional outcome after SCI. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention 2.0)

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15 pages, 1327 KiB

Open AccessReview

Senolytics: A Novel Strategy for Neuroprotection in ALS?

by Alexandra Maximova, Eryn L. Werry and Michael Kassiou

Int. J. Mol. Sci. 2021, 22(21), 12078; https://doi.org/10.3390/ijms222112078 - 08 Nov 2021

Cited by 6 | Viewed by 3316

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system (CNS) cells, leading to excess neuroinflammation and neurodegeneration. Damage to the upper and lower motor neurons results in neural and muscular dysfunction, leading to death most often due to respiratory paralysis. A new therapeutic strategy is targeting glial cells affected by senescence, which contribute to motor neuron degeneration. Whilst this new therapeutic approach holds much promise, it is yet to be trialled in ALS-relevant preclinical models and needs to be designed carefully to ensure selectivity. This review summarizes the pathways involved in ALS-related senescence, as well as known senolytic agents and their mechanisms of action, all of which may inform strategies for ALS-focused drug discovery efforts. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention 2.0)

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16 pages, 3197 KiB

Open AccessReview

Migraine: Calcium Channels and Glia

by Marta Kowalska, Michał Prendecki, Thomas Piekut, Wojciech Kozubski and Jolanta Dorszewska

Int. J. Mol. Sci. 2021, 22(5), 2688; https://doi.org/10.3390/ijms22052688 - 07 Mar 2021

Cited by 14 | Viewed by 5604

Abstract

Migraine is a common neurological disease that affects about 11% of the adult population. The disease is divided into two main clinical subtypes: migraine with aura and migraine without aura. According to the neurovascular theory of migraine, the activation of the trigeminovascular system [...] Read more.

Migraine is a common neurological disease that affects about 11% of the adult population. The disease is divided into two main clinical subtypes: migraine with aura and migraine without aura. According to the neurovascular theory of migraine, the activation of the trigeminovascular system (TGVS) and the release of numerous neuropeptides, including calcitonin gene-related peptide (CGRP) are involved in headache pathogenesis. TGVS can be activated by cortical spreading depression (CSD), a phenomenon responsible for the aura. The mechanism of CSD, stemming in part from aberrant interactions between neurons and glia have been studied in models of familial hemiplegic migraine (FHM), a rare monogenic form of migraine with aura. The present review focuses on those interactions, especially as seen in FHM type 1, a variant of the disease caused by a mutation in CACNA1A, which encodes the α1A subunit of the P/Q-type voltage-gated calcium channel. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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35 pages, 849 KiB

Open AccessReview

Copper Dyshomeostasis in Neurodegenerative Diseases—Therapeutic Implications

by Grażyna Gromadzka, Beata Tarnacka, Anna Flaga and Agata Adamczyk

Int. J. Mol. Sci. 2020, 21(23), 9259; https://doi.org/10.3390/ijms21239259 - 04 Dec 2020

Cited by 123 | Viewed by 8462

Abstract

Copper is one of the most abundant basic transition metals in the human body. It takes part in oxygen metabolism, collagen synthesis, and skin pigmentation, maintaining the integrity of blood vessels, as well as in iron homeostasis, antioxidant defense, and neurotransmitter synthesis. It [...] Read more.

Copper is one of the most abundant basic transition metals in the human body. It takes part in oxygen metabolism, collagen synthesis, and skin pigmentation, maintaining the integrity of blood vessels, as well as in iron homeostasis, antioxidant defense, and neurotransmitter synthesis. It may also be involved in cell signaling and may participate in modulation of membrane receptor-ligand interactions, control of kinase and related phosphatase functions, as well as many cellular pathways. Its role is also important in controlling gene expression in the nucleus. In the nervous system in particular, copper is involved in myelination, and by modulating synaptic activity as well as excitotoxic cell death and signaling cascades induced by neurotrophic factors, copper is important for various neuronal functions. Current data suggest that both excess copper levels and copper deficiency can be harmful, and careful homeostatic control is important. This knowledge opens up an important new area for potential therapeutic interventions based on copper supplementation or removal in neurodegenerative diseases including Wilson’s disease (WD), Menkes disease (MD), Alzheimer’s disease (AD), Parkinson’s disease (PD), and others. However, much remains to be discovered, in particular, how to regulate copper homeostasis to prevent neurodegeneration, when to chelate copper, and when to supplement it. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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19 pages, 1474 KiB

Open AccessReview

Rethinking Intellectual Disability from Neuro- to Astro-Pathology

by Álvaro Fernández-Blanco and Mara Dierssen

Int. J. Mol. Sci. 2020, 21(23), 9039; https://doi.org/10.3390/ijms21239039 - 27 Nov 2020

Cited by 12 | Viewed by 3490

Abstract

Neurodevelopmental disorders arise from genetic and/or from environmental factors and are characterized by different degrees of intellectual disability. The mechanisms that govern important processes sustaining learning and memory, which are severely affected in intellectual disability, have classically been thought to be exclusively under [...] Read more.

Neurodevelopmental disorders arise from genetic and/or from environmental factors and are characterized by different degrees of intellectual disability. The mechanisms that govern important processes sustaining learning and memory, which are severely affected in intellectual disability, have classically been thought to be exclusively under neuronal control. However, this vision has recently evolved into a more integrative conception in which astroglia, rather than just acting as metabolic supply and structural anchoring for neurons, interact at distinct levels modulating neuronal communication and possibly also cognitive processes. Recently, genetic tools have made it possible to specifically manipulate astrocyte activity unraveling novel functions that involve astrocytes in memory function in the healthy brain. However, astrocyte manipulation has also underscored potential mechanisms by which dysfunctional astrocytes could contribute to memory deficits in several neurodevelopmental disorders revealing new pathogenic mechanisms in intellectual disability. Here, we review the current knowledge about astrocyte dysfunction that might contribute to learning and memory impairment in neurodevelopmental disorders, with special focus on Fragile X syndrome and Down syndrome. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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12 pages, 583 KiB

Open AccessReview

Vesicular Transport of Encapsulated microRNA between Glial and Neuronal Cells

by Walter J. Lukiw and Aileen I. Pogue

Int. J. Mol. Sci. 2020, 21(14), 5078; https://doi.org/10.3390/ijms21145078 - 18 Jul 2020

Cited by 26 | Viewed by 3470

Abstract

Exosomes (EXs) and extracellular microvesicles (EMVs) represent a diverse assortment of plasma membrane-derived nanovesicles, 30–1000 nm in diameter, released by all cell lineages of the central nervous system (CNS). They are examples of a very active and dynamic form of extracellular communication and [...] Read more.

Exosomes (EXs) and extracellular microvesicles (EMVs) represent a diverse assortment of plasma membrane-derived nanovesicles, 30–1000 nm in diameter, released by all cell lineages of the central nervous system (CNS). They are examples of a very active and dynamic form of extracellular communication and the conveyance of biological information transfer essential to maintain homeostatic neurological functions and contain complex molecular cargoes representative of the cytoplasm of their cells of origin. These molecular cargoes include various mixtures of proteins, lipids, proteolipids, cytokines, chemokines, carbohydrates, microRNAs (miRNA) and messenger RNAs (mRNA) and other components, including end-stage neurotoxic and pathogenic metabolic products, such as amyloid beta (Aβ) peptides. Brain microglia, for example, respond to both acute CNS injuries and degenerative diseases with complex reactions via the induction of a pro-inflammatory phenotype, and secrete EXs and EMVs enriched in selective pathogenic microRNAs (miRNAs) such as miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155, and others that are known to promote neuro-inflammation, induce complement activation, disrupt innate–immune signaling and deregulate the expression of neuron-specific phosphoproteins involved in neurotropism and synaptic signaling. This communication will review our current understanding of the trafficking of miRNA-containing EXs and EMVs from astrocytes and “activated pro-inflammatory” microglia to target neurons in neurodegenerative diseases with an emphasis on Alzheimer’s disease wherever possible. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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