Journal Description
Neuroglia
Neuroglia
is an international, peer-reviewed, open access journal on Neuroscience published quarterly online by MDPI.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 29.8 days after submission; acceptance to publication is undertaken in 4.2 days (median values for papers published in this journal in the second half of 2023).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Latest Articles
The Relevance of Astrocytic Cell Culture Models for Neuroinflammation in Neurodegeneration Research
Neuroglia 2024, 5(1), 27-49; https://doi.org/10.3390/neuroglia5010003 - 29 Feb 2024
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Astrocytes are the predominant glial cells that provide essential support to neurons and promote microenvironment changes in neuropathological states. Astrocyte and astrocytic-like cell culture have substantially contributed to elucidating the molecular pathways involved in key glial roles, including those relevant to neurodevelopment, brain
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Astrocytes are the predominant glial cells that provide essential support to neurons and promote microenvironment changes in neuropathological states. Astrocyte and astrocytic-like cell culture have substantially contributed to elucidating the molecular pathways involved in key glial roles, including those relevant to neurodevelopment, brain physiology and metabolism, which are not readily accessible with traditional approaches. The in vitro methodology has also been applied to neuroinflammatory and neurodegeneration contexts, revealing cellular changes involved in brain dysfunction. Astrocytes studies in culture started with primary cell approaches using embryonic and postmortem tissue. Further developments included newborn rodent primary cells, cell lines and immortalized astrocytes, which resulted in homogeneous cell-type preparations grown on flat surfaces. To overcome some in vitro shortcomings, tridimensional bioprinted models and organoid culture enabled the mimicking of tissue cellular arrangements and, above these achievements, complex astrocyte cell culture can be generated from induced pluripotent stem cells (iPSCs) to model diseases. These unprecedented breakthroughs allowed the development of platforms to test new therapies in brain cells derived from human material noninvasively obtained from live patients. In this work, we reviewed the most studied astrocytic cell models for discussing limitations, advantages and reliable experimental readouts for neuroinflammation in neurodegeneration research.
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Open AccessReview
The Role of Neuroglia in Administrating Nerve Blockers and Anesthesia to Patients
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Anjali Patel, Raja Al-Bahou, Rajvi Thakkar, Drashti Patel, Devon Foster, Jonathan Benjamin, Marian Pedreira and Brandon Lucke-Wold
Neuroglia 2024, 5(1), 13-26; https://doi.org/10.3390/neuroglia5010002 - 29 Jan 2024
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Dysfunction of the neuroglia can have profound consequences on the blood–brain barrier (BBB). Studies have shown that the disruption of astrocytic–endothelial interaction can compromise the permeability of BBB and its effectiveness in selectively regulating the exchange of substances. Microglia have recently been recognized
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Dysfunction of the neuroglia can have profound consequences on the blood–brain barrier (BBB). Studies have shown that the disruption of astrocytic–endothelial interaction can compromise the permeability of BBB and its effectiveness in selectively regulating the exchange of substances. Microglia have recently been recognized to have a significant role in the initiation of chronic pain and in its interactions with various nerve blockers and anesthetic agents. Microglia have a role in pain resolution via a pathway that involves Cannabinoid receptor type 2 activation and MAP kinase phosphorylation. Understanding the role of these cells in the context of neuropathic pain and neurological disorders can aid in improving clinical outcomes and the challenging nature of managing pain. Advancing studies have proposed pharmacological and genetic modulation of microglia as a potential treatment option for patients with chronic pain.
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Open AccessPerspective
Contribution of Small Extracellular Vesicles from Schwann Cells and Satellite Glial Cells to Pain Processing
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Parisa Gazerani
Neuroglia 2024, 5(1), 1-12; https://doi.org/10.3390/neuroglia5010001 - 28 Jan 2024
Abstract
Extracellular vesicles (EVs), including exosomes and microvesicles, are membrane-bound particles released by cells into extracellular space. These vesicles carry various molecules, such as proteins and lipids, and can serve as mediators of intercellular communication. EVs have been implicated in the communication between different
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Extracellular vesicles (EVs), including exosomes and microvesicles, are membrane-bound particles released by cells into extracellular space. These vesicles carry various molecules, such as proteins and lipids, and can serve as mediators of intercellular communication. EVs have been implicated in the communication between different cell types in the nervous system, for instance, the neurons and glial cells of the central nervous system (CNS) and peripheral nervous system (PNS). Satellite glial cells (SGCs) surround and support neurons in the sensory ganglia of the PNS, and it has been proposed that the EVs released by SGCs may contribute to the processing of pain-related signals and features. This includes the modulation of neuronal activity, the release of pro-inflammatory signaling molecules, and sensitization. A noticeable finding is that EVs can transfer bioactive molecules, including proteins and microRNAs (miRNAs), between cells, influencing cellular functions such as gene expression regulation involved in the transmission and modulation of pain signals. Schwann cells (SCs) also release EVs. SC-derived EVs sequester TNFR1, influencing TNFα activity and regulating neuroinflammation in peripheral nerve injuries. Understanding peripheral glia’s EVs role in pain processing is an emerging area in neuroscience. Here, the latest findings, challenges, and potential are presented to encourage future research.
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(This article belongs to the Special Issue Exclusive Papers Collection of Editorial Board Members in Neuroglia)
Open AccessReview
Protoplasmic Perivascular Astrocytes Play a Crucial Role in the Development of Enlarged Perivascular Spaces in Obesity, Metabolic Syndrome, and Type 2 Diabetes Mellitus
by
Melvin R. Hayden
Neuroglia 2023, 4(4), 307-328; https://doi.org/10.3390/neuroglia4040021 - 01 Dec 2023
Cited by 1
Abstract
Astrocytes (ACs) are the most abundant cells in the brain and, importantly, are the master connecting and communicating cells that provide structural and functional support for brain cells at all levels of organization. Further, they are recognized as the guardians and housekeepers of
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Astrocytes (ACs) are the most abundant cells in the brain and, importantly, are the master connecting and communicating cells that provide structural and functional support for brain cells at all levels of organization. Further, they are recognized as the guardians and housekeepers of the brain. Protoplasmic perivascular astrocyte endfeet and their basal lamina form the delimiting outermost barrier (glia limitans) of the perivascular spaces in postcapillary venules and are important for the clearance of metabolic waste. They comprise the glymphatic system, which is critically dependent on proper waste removal by the pvACef polarized aquaporin-4 water channels. Also, the protoplasmic perisynaptic astrocyte endfeet (psACef) are important in cradling the neuronal synapses that serve to maintain homeostasis and serve a functional and supportive role in synaptic transmission. Enlarged perivascular spaces (EPVS) are emerging as important aberrant findings on magnetic resonance imaging (MRI), and are associated with white matter hyperintensities, lacunes, and aging, and are accepted as biomarkers for cerebral small vessel disease, increased obesity, metabolic syndrome, and type 2 diabetes. Knowledge is exponentially expanding regarding EPVS along with the glymphatic system, since EPVS are closely associated with impaired glymphatic function and waste removal from the brain to the cerebrospinal fluid and systemic circulation. This review intends to focus on how the pvACef play a crucial role in the development of EPVS.
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(This article belongs to the Special Issue Exclusive Papers Collection of Editorial Board Members in Neuroglia)
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Open AccessArticle
Aging-Related Changes in Expression and Function of Glutamate Transporters in Rat Spinal Cord Astrocytes
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Shiksha Sharan, Bhanu Prakash Tewari and Preeti G. Joshi
Neuroglia 2023, 4(4), 290-306; https://doi.org/10.3390/neuroglia4040020 - 24 Nov 2023
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Astrocytes make up the predominant cell population among glial cells in the mammalian brain, and they play a vital role in ensuring its optimal functioning. They promote neuronal health and survival and protect neurons from glutamate-induced excitotoxicity. In the spinal cord’s dorsal horn
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Astrocytes make up the predominant cell population among glial cells in the mammalian brain, and they play a vital role in ensuring its optimal functioning. They promote neuronal health and survival and protect neurons from glutamate-induced excitotoxicity. In the spinal cord’s dorsal horn (DH) and ventral horn (VH) regions, astrocytes serve crucial roles. Notably, VH motor neurons exhibit a heightened sensitivity to glutamate-induced damage. It is posited that this selective sensitivity could be related to their localized presence within the VH, where astrocytes possess a distinct set of mechanisms for managing glutamate. As organisms age, the risk of damage from glutamate increases, indicating a potential decline in the efficiency of astrocytic glutamate regulation. Our research involved an analysis of astrocytic structure, glutamate transporter levels, and glutamate uptake capabilities within the DH and VH through immunohistochemical methods, protein analysis via Western blot, and patch-clamp studies in electrophysiology. The investigations revealed a decrease in both the number and coverage of astroglia in the spinal cord, more so within the VH as aging progressed. Notably, levels of the excitatory amino acid transporters 1 and 2 (EAAT1 and EAAT2) also decreased with age, particularly within the VH. Patch-clamp analyses of astrocytes from both spinal regions confirmed a significant reduction in glutamate uptake activity as age advanced, indicating an age-related impairment in glutamate processing. The findings indicate aging leads to distinct changes in DH and VH astrocytes, impairing their glutamate management abilities, which could contribute significantly to the development of late-onset neurodegenerative conditions.
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Open AccessArticle
Comparison of the Transduction Capacity of AAV5 and AAV PHP.eB Serotypes in Hippocampus Astroglia
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Anastasia Borodinova, Victor Ierusalimsky and Pavel Balaban
Neuroglia 2023, 4(4), 275-289; https://doi.org/10.3390/neuroglia4040019 - 01 Nov 2023
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In the present study, we compared the astrocyte-transducing potential of the relatively novel engineered AAV PHP.eB serotype and the well-examined conventional AAV5 serotype. We generated the AAV-based genetic constructs with membrane-bound fluorescent markers under the control of the astroglial promoter GfaABC1D to target
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In the present study, we compared the astrocyte-transducing potential of the relatively novel engineered AAV PHP.eB serotype and the well-examined conventional AAV5 serotype. We generated the AAV-based genetic constructs with membrane-bound fluorescent markers under the control of the astroglial promoter GfaABC1D to target astrocytes in vivo, either via local injection into the hippocampus (AAV5, AAV PHP.eB) or via systemic injection in the retro-orbital venous sinus (AAV PHP.eB). We collected new data on the transduction properties of locally injected PHP.eB and AAV5 viruses. A morphological examination and immunostainings of mouse brain slices revealed a dose-dependent shift of cellular tropism for locally injected PHP.eB from astroglial to astroglial-neuronal as the concentration increased. When the high doses of PHP.eB viruses were administered systemically, we observed strong astrocyte transduction throughout the brain, as confirmed by the morphological examination and GFAP immunostaining. AAV5 exhibited consistent astrocytic expression in all tested concentrations. The obtained results suggest that AAV5 is more suitable for astrocyte targeting in routine stereotaxic viral injection experiments. The widely used engineered PHP.eB capsid was originally designed for the transduction of both neurons and glia. Dual cellular tropism of PHP.eB viruses, observed using different doses and different delivery protocols (local vs. systemic), suggests that the usage of AAV5 is more reliable for astrocyte labeling and that intrahippocampal injection is more suitable than systemic injection for the preferential labeling of hippocampal astroglia.
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Open AccessReview
The Signaling of Neuregulin-Epidermal Growth Factor Receptors and Its Impact on the Nervous System
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Marzia Tagliaferro and Donatella Ponti
Neuroglia 2023, 4(4), 253-274; https://doi.org/10.3390/neuroglia4040018 - 13 Oct 2023
Abstract
The activation of members of the Epidermal Growth Factor Receptor (EGFR) family (including ErbB) triggers pathways that have significant effects on cellular processes and have profound consequences both in physiological and pathological conditions. Within the nervous system, the neuregulin (NRG)/ErbB3 signaling plays a
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The activation of members of the Epidermal Growth Factor Receptor (EGFR) family (including ErbB) triggers pathways that have significant effects on cellular processes and have profound consequences both in physiological and pathological conditions. Within the nervous system, the neuregulin (NRG)/ErbB3 signaling plays a crucial role in promoting the formation and maturation of excitatory synapses. Noteworthy is ErbB3, which is actively involved in the process of cerebellar lamination and myelination. All members of the ErbB-family, in particular ErbB3, have been observed within the nuclei of various cell types, including both full-length receptors and alternative variants. One of these variants was detected in Schwann cells and in glioblastoma primary cells where it showed a neuregulin-dependent expression. It binds to promoters’ chromatin associated with genes, like ezrin, involved in the formation of Ranvier’s node. Its nucleolar localization suggests that it may play a role in ribosome biogenesis and in cell proliferation. The regulation of ErbB3 expression is a complex and dynamic process that can be influenced by different factors, including miRNAs. This mechanism appears to play a significant role in glioblastoma and is often associated with a poor prognosis. Altogether, the targeting of ErbB3 has emerged as an active area of research in glioblastoma treatment. These findings highlight the underappreciated role of ErbB3 as a significant receptor that can potentially play a pivotal role in diverse pathologies, implying the existence of a shared and intricate mechanism that warrants further investigation.
Full article
(This article belongs to the Special Issue Glioblastoma (GBM) Brain Tumor Invasion and Consequences on Diagnosis, Clinical Strategies and Therapy)
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Open AccessReview
GABAA-ρ Receptors in the CNS: Their Functional, Pharmacological, and Structural Properties in Neurons and Astroglia
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Abraham Rosas-Arellano, Argel Estrada-Mondragón, Ataúlfo Martínez-Torres and Daniel Reyes-Haro
Neuroglia 2023, 4(4), 239-252; https://doi.org/10.3390/neuroglia4040017 - 08 Oct 2023
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Gamma-aminobutyric acid (GABA) is known as the main inhibitory transmitter in the central nervous system (CNS), where it hyperpolarizes mature neurons through activation of GABAA receptors, pentameric complexes assembled by combination of subunits (α1–6, β1–3, γ1–3, δ, ε, θ, π and ρ1–3).
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Gamma-aminobutyric acid (GABA) is known as the main inhibitory transmitter in the central nervous system (CNS), where it hyperpolarizes mature neurons through activation of GABAA receptors, pentameric complexes assembled by combination of subunits (α1–6, β1–3, γ1–3, δ, ε, θ, π and ρ1–3). GABAA-ρ subunits were originally described in the retina where they generate non-desensitizing Cl- currents that are insensitive to bicuculline and baclofen. However, now is known that they are widely expressed throughout the brain including glial cells. For example, whole-cell patch-clamp recordings demonstrated the functional expression of GABAA-ρ receptors in primary cultures of cerebellar astrocytes, as well as in cerebellar ependymal cells and striatal astrocytes. In these cells GABA-currents were partially blocked by TPMPA and insensitive to barbiturates. These receptors are proposed to be involved in extrasynaptic communication and dysfunction of the signaling is accompanied by reduced expression of GABAA-ρ receptors in Huntington’s disease and autism spectrum disorders (ASD). Thus, the aim of this review is to present an overview about GABAA-ρ receptors including their structure and function, as well as their importance in the excitatory/inhibitory (E/I) balance in neurodevelopment and in disease.
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Open AccessArticle
Combination of Engineered Expression of Polysialic Acid on Transplanted Schwann Cells and in Injured Rat Spinal Cord Promotes Significant Axonal Growth and Functional Recovery
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Fangyou Gao, Yi Zhang, Dongsheng Wu, Juan Luo, Svetlana Gushchina and Xuenong Bo
Neuroglia 2023, 4(4), 222-238; https://doi.org/10.3390/neuroglia4040016 - 23 Sep 2023
Abstract
Providing cellular support and modifying the glial scar around the lesion are two key strategies for promoting axonal regeneration after spinal cord injury. We showed previously that over-expressing polysialic acid (PSA) on Schwann cells (SCs) by lentiviral vector (LV)-mediated expression of polysialyltransferase (PST)
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Providing cellular support and modifying the glial scar around the lesion are two key strategies for promoting axonal regeneration after spinal cord injury. We showed previously that over-expressing polysialic acid (PSA) on Schwann cells (SCs) by lentiviral vector (LV)-mediated expression of polysialyltransferase (PST) facilitated their integration and migration in the injured spinal cord. We also showed that PSA over-expression in the injured spinal cord modified the glial scar and promoted the growth of ascending sensory axons. In this study, we combined the PST/SC transplantation with LV/PST injection in spinal cords after dorsal column transection and found the combined treatments led to faster and more profound locomotor functional recovery compared with animals receiving combined GFP/SC transplantation with LV/GFP injection. Histological examination showed significantly more injured corticospinal axons growing close to the lesion/transplant borders and into the caudal spinal cord in the PST group than in the GFP group. We also found over -expressing PSA around the lesion site did not cause allodynia and hyperalgesia in our injury model. These results demonstrate the promising therapeutic benefit of over-expressing PSA in transplanted SCs and spinal cord in promoting axonal growth and restoring motor function.
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(This article belongs to the Special Issue Exclusive Papers Collection of Editorial Board Members in Neuroglia)
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Open AccessReview
The Role of Astrocytes and Blood–Brain Barrier Disruption in Alzheimer’s Disease
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João Victor R. Cruz, Carolina Batista, Luan Pereira Diniz and Fabio A. Mendes
Neuroglia 2023, 4(3), 209-221; https://doi.org/10.3390/neuroglia4030015 - 20 Aug 2023
Cited by 1
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The blood–brain barrier (BBB) is a highly intricate neurovascular structure that plays a crucial role in maintaining neural homeostasis by selectively allowing certain molecules to enter the central nervous system (CNS). However, in the context of Alzheimer’s Disease (AD), a progressive neurodegenerative disorder
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The blood–brain barrier (BBB) is a highly intricate neurovascular structure that plays a crucial role in maintaining neural homeostasis by selectively allowing certain molecules to enter the central nervous system (CNS). However, in the context of Alzheimer’s Disease (AD), a progressive neurodegenerative disorder characterized by a gradual decline in cognitive function, the BBB’s functionality becomes impaired. This impairment leads to the breakdown of the barrier and disrupts its ability to regulate molecular transport effectively. Consequently, cellular infiltration into the CNS occurs, along with aberrant signaling and clearance of molecules, ultimately contributing to neurological deficits. One of the key factors implicated in the failure of amyloid-beta (Aβ) transport, a hallmark of AD, is the decreased expression of low-density lipoprotein receptor-related protein 1 (LRP1). LRP1 plays a crucial role in facilitating the transport of Aβ across the BBB. Additionally, the increased levels of the receptor for advanced glycation end products (RAGE) further contribute to the deregulation of the BBB in AD. These molecular imbalances significantly impact Aβ clearance and contribute to the development and progression of AD. In this review, we aimed to summarize the critical aspects of Aβ transporters in the BBB that become dysfunctional during the pathogenesis of AD.
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Open AccessReview
Overview of the Molecular Modalities and Signaling Pathways Intersecting with β-Amyloid and Tau Protein in Alzheimer’s Disease
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Ahmed M. Elshazly, Melanie M. Sinanian, Diaaeldin M. Elimam and Sherin Zakaria
Neuroglia 2023, 4(3), 191-208; https://doi.org/10.3390/neuroglia4030014 - 30 Jul 2023
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Alzheimer’s disease (AD) is one of the major causes of dementia and its incidence represents approximately 60–70% of all dementia cases worldwide. Many theories have been proposed to describe the pathological events in AD, including deterioration in cognitive function, accumulation of β-amyloid, and
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Alzheimer’s disease (AD) is one of the major causes of dementia and its incidence represents approximately 60–70% of all dementia cases worldwide. Many theories have been proposed to describe the pathological events in AD, including deterioration in cognitive function, accumulation of β-amyloid, and tau protein hyperphosphorylation. Infection as well as various cellular molecules, such as apolipoprotein, micro-RNA, calcium, ghrelin receptor, and probiotics, are associated with the disruption of β-amyloid and tau protein hemostasis. This review gives an overview on the integrative cellular and signaling molecules that could play a complementary role in the dysregulation of β-amyloid and tau proteins.
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Open AccessEditorial
Unraveling the Critical Mechanisms and Functions of Neuroglia in Spinal Cord Injuries
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Chih-Wei Zeng
Neuroglia 2023, 4(3), 188-190; https://doi.org/10.3390/neuroglia4030013 - 24 Jul 2023
Cited by 1
Abstract
In the dynamic landscape of neuroscience and regenerative medicine, the pivotal role of neuroglia, or glial cells, is increasingly being recognized [...]
Full article
(This article belongs to the Special Issue Regenerative Medicine: The Mechanism and Role of Neuroglia after Spinal Cord Injury)
Open AccessArticle
A Human Microglial Cell Line Expresses γ-Aminobutyric Acid (GABA) Receptors and Responds to GABA and Muscimol by Increasing Production of IL-8
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Ashley Wagner, Zhimin Yan and Marianna Kulka
Neuroglia 2023, 4(3), 172-187; https://doi.org/10.3390/neuroglia4030012 - 28 Jun 2023
Abstract
Gamma-aminobutyric acid (GABA) is an essential neurotransmitter and an important regulator of neuroinflammation and disease. Microglia are important immune cells in the brain that express GABA receptors (GABAR) and respond to both GABA and GABAR agonists, yet the effect of GABA on microglial
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Gamma-aminobutyric acid (GABA) is an essential neurotransmitter and an important regulator of neuroinflammation and disease. Microglia are important immune cells in the brain that express GABA receptors (GABAR) and respond to both GABA and GABAR agonists, yet the effect of GABA on microglial inflammatory responses is unclear. We hypothesized that GABA and GABAR agonists might modify the activation of a human microglial cell line (HMC3). We further hypothesized that Amanita muscaria extract (AME-1), which contained GABAR agonists (GABA and muscimol), would similarly stimulate HMC3. Ligand-gated GABAR (GABAAR) and G protein-coupled GABAR (GABABR) subunit expression was analyzed by qRT-PCR, metabolic activity was determined by nicotinamide adenine dinucleotide (NADH)-dependent oxidoreductase assay (XTT), reactive oxygen species (ROS) generation was analyzed by 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA), and interleukin-8 (IL-8) production was analyzed by an enzyme-linked immunosorbent assay (ELISA). HMC3 expressed several neuroreceptors such as subunits of the GABAA receptor (GABAAR). HMC3 constitutively produce IL-8 and ROS. Both muscimol and GABA stimulated HMC3 to produce more IL-8 but had no effect on constitutive ROS production. GABA and muscimol altered the morphology and Iba1 localization of HMC3. GABA, but not muscimol, increased HMC3 metabolic activity. Similarly, AME-1 induced HMC3 to produce more IL-8 but not ROS and altered cell morphology and Iba1 localization. GABA induction of IL-8 was blocked by bicuculline, an antagonist of GABAAR. AME-1-induced production of IL-8 was not blocked by bicuculline, suggesting that AME-1’s effect on HMC3 was independent of GABAAR. In conclusion, these data show that GABA and GABA agonists stimulate HMC3 to increase their production of IL-8. Mixtures that contain GABA and muscimol, such as AME-1, have similar effects on HMC3 that are independent of GABAAR.
Full article
(This article belongs to the Special Issue New Insights into the Anti-inflammatory Role of Microglia)
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Open AccessArticle
Glucose Transporter-2 Regulation of Male versus Female Hypothalamic Astrocyte MAPK Expression and Activation: Impact of Glucose
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Madhu Babu Pasula, Sagor C. Roy, Khaggeswar Bheemanapally, Paul W. Sylvester and Karen P. Briski
Neuroglia 2023, 4(3), 158-171; https://doi.org/10.3390/neuroglia4030011 - 21 Jun 2023
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The plasma membrane glucose transporter (GLUT)-2 is unique among GLUT family proteins in that it also functions as a glucose sensor. GLUT2 imposes sex-dimorphic control of hypothalamic astrocyte glucose storage and catabolism by unknown mechanisms. Mitogen-activated protein kinase (MAPK) signaling cascades operate within
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The plasma membrane glucose transporter (GLUT)-2 is unique among GLUT family proteins in that it also functions as a glucose sensor. GLUT2 imposes sex-dimorphic control of hypothalamic astrocyte glucose storage and catabolism by unknown mechanisms. Mitogen-activated protein kinase (MAPK) signaling cascades operate within stress-sensitive signal transduction pathways. The present study employed an established primary astrocyte culture model and gene knockdown tools to investigate whether one or more of the three primary MAP kinase families are regulated by GLUT2. GLUT2 gene knockdown caused opposing adjustments in total ERK1/2 proteins in glucose-supplied male versus female astrocytes, augmenting or reducing the mean phosphorylated/total protein ratio for 44 and 42 kDa variants in these sexes. Glucose deprivation amplified this ratio for both ERK1/2 variants, albeit by a larger magnitude in males; GLUT2 siRNA exacerbated this stimulatory response in males only. Phosphorylated/total p38 MAPK protein ratios were up-regulated by GLUT2 knockdown in male, but not female astrocytes. Glucose-deprived astrocytes exhibited no change (male) or reduction (female) in this ratio after GLUT2 gene silencing. GLUT2 siRNA increased the phosphorylated/total protein ratio for 54 and 46 kDa SAPK/JNK proteins in each sex when glucose was present. However, glucose withdrawal suppressed (male) or amplified (female) these ratios, while GLUT2 knockdown attenuated these inverse responses. The results show that GLUT2 inhibits ERK1/2, p38, and SAPK/JNK MAPK activity in male astrocytes, but differentially stimulates and inhibits activity of these signaling pathways in female hypothalamic astrocytes. Glucoprivation induces divergent adjustments in astrocyte p38 MAPK and SAPK/JNK activities. The findings demonstrate a stimulatory role for GLUT2 in p38 MAPK activation in glucose-starved female astrocytes, but it can act as either an inhibitor or inducer of SAPK/JNK activation in glucose-deprived male versus female glial cells, respectively.
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Open AccessArticle
Focused Ultrasound-Mediated Blood–Brain Barrier Opening Best Promotes Neuroimmunomodulation through Brain Macrophage Redistribution
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Alina R. Kline-Schoder, Rebecca L. Noel, Hemali Phatnani, Vilas Menon and Elisa E. Konofagou
Neuroglia 2023, 4(2), 141-157; https://doi.org/10.3390/neuroglia4020010 - 31 May 2023
Cited by 2
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Neuroimmunomodulation is a promising form of drug-free treatment for neurological diseases ranging from Alzheimer’s disease to depression. The evidence supporting the efficacy of focused ultrasound (FUS) neuroimmunomodulation is encouraging; however, the method has yet to be standardized, and its mechanism remains poorly understood.
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Neuroimmunomodulation is a promising form of drug-free treatment for neurological diseases ranging from Alzheimer’s disease to depression. The evidence supporting the efficacy of focused ultrasound (FUS) neuroimmunomodulation is encouraging; however, the method has yet to be standardized, and its mechanism remains poorly understood. Methods of FUS neuroimmunomodulation can be categorized into three paradigms based on the parameters used. In the first paradigm, focused ultrasound blood–brain barrier opening (FUS-BBBO) combines FUS with microbubbles (MB) to transiently and safely induce BBB opening. In the second paradigm, focused ultrasound neuromodulation (FUS-N) harnesses the acoustic effects of FUS alone (without MB). In the third paradigm, focused ultrasound with microbubbles without BBBO (FUS + MB) combines MB with FUS below the BBBO pressure threshold—harnessing the mechanical effects of FUS without opening the barrier. Due to the recent evidence of brain macrophage modulation in response to FUS-BBBO, we provide the first direct comparison of brain macrophage modulation between all three paradigms both in the presence and absence of Alzheimer’s disease (AD) pathology. Flow cytometry and single-cell sequencing are employed to identify FUS-BBBO as the FUS paradigm, which maximizes brain macrophage modulation, including an increase in the population of neuroprotective, disease-associated microglia and direct correlation between treatment cavitation dose and brain macrophage phagocytosis. Next, we combine spatial and single-cell transcriptomics with immunohistochemical validation to provide the first characterization of brain macrophage distribution in response to FUS-BBBO. Given their relevance within neurodegeneration and perturbation response, we emphasize the analysis of three brain macrophage populations—disease- and interferon-associated microglia and central-nervous-system-associated macrophages. We find and validate the redistribution of each population with an overall trend toward increased interaction with the brain–cerebrospinal fluid barrier (BCSFB) after FUS-BBBO, an effect that is found to be more pronounced in the presence of disease pathology. This study addresses the prior lack of FUS neuroimmunomodulation paradigm optimization and mechanism characterization, identifying that FUS-BBBO best modulates brain macrophage response via complex redistribution.
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Open AccessPerspective
The Role of Lactylation in Mental Illness: Emphasis on Microglia
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Adonis Sfera, Carolina Klein, Johnathan J. Anton, Zisis Kozlakidis and Christina V. Andronescu
Neuroglia 2023, 4(2), 119-140; https://doi.org/10.3390/neuroglia4020009 - 16 May 2023
Cited by 2
Abstract
A paradigm shift is currently taking place in the etiopathogenesis of neuropsychiatric disorders as immunometabolism is replacing the earlier neurotransmitter model. According to the new concept, cellular bioenergetics drives information processing in the central nervous system; therefore, neuropathology is conceptualized as a direct
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A paradigm shift is currently taking place in the etiopathogenesis of neuropsychiatric disorders as immunometabolism is replacing the earlier neurotransmitter model. According to the new concept, cellular bioenergetics drives information processing in the central nervous system; therefore, neuropathology is conceptualized as a direct consequence of impaired metabolism. Along the same lines, endoplasmic reticulum stress and gut barrier dysfunction are emerging as novel targets in schizophrenia and affective disorders, linking immune responses to cellular distress. Furthermore, microglia, the brain’s innate immune cells, acquire energy through oxidative phosphorylation, while in the resting state, and glycolysis upon activation, contributing to lactate accumulation and reduced brain pH. The same metabolic signature characterizes neuropsychiatric disorders as the central nervous system derives adenosine triphosphate from aerobic glycolysis, upregulating lactate and generating an acidic environment. Although known for over three decades, the link between dysmetabolism and neuropathology was poorly defined until the discovery of brain-resident innate lymphoid cells, including natural killer cells, and lactylation of histone and nonhistone proteins. In this perspective article, we examine three anti-inflammatory microglial systems relevant for neuropsychiatry: lactate, oxytocin, and the aryl hydrocarbon receptor. We also discuss potential interventions for restoring microglial homeostasis.
Full article
(This article belongs to the Special Issue New Insights into the Anti-inflammatory Role of Microglia)
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Open AccessArticle
Q1VA, a Synthetic Chalcone, Induces Apoptosis and Decreases Invasion on Primary Culture of Human Glioblastoma
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Anderson Togni, Tetsade Piermartiri, Luiz Felipe Schmitz de Souza, Louise Domeneghi Chiaradia Delatorre, Ricardo José Nunes, Carla Inês Tasca and Cláudia Beatriz Nedel
Neuroglia 2023, 4(2), 102-118; https://doi.org/10.3390/neuroglia4020008 - 30 Apr 2023
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Glioblastoma (GBM) is the most commonly occurring type of primary tumor of the central nervous system (CNS) and is considered the worst type of glioma. Despite the current standard treatment for newly diagnosed GBM, which involves surgery followed by chemotherapy with temozolomide (TMZ)
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Glioblastoma (GBM) is the most commonly occurring type of primary tumor of the central nervous system (CNS) and is considered the worst type of glioma. Despite the current standard treatment for newly diagnosed GBM, which involves surgery followed by chemotherapy with temozolomide (TMZ) and radiation therapy, the average survival time for patients with GBM is only about 15 months. This is due to GBM’s tendency to recur, its high proliferative rates, its ability to evade apoptosis, and its ability to invade healthy tissue. Therefore, it is crucial to explore new treatment options for GBM. This study investigated the potential anticancer activities of a new series of synthetic chalcones, which are natural compounds found in the biosynthesis of flavonoids in plants. Primary cell culture of glioblastoma (GBM1) from surgical resection was used to evaluate the effects of synthetic chalcones on viability, cell death, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), cell cycle, and invasion. One chalcone, Q1VA (at concentrations of 10, 50, and 100 μM for 24 h) induced cytotoxicity by increasing apoptosis levels and depolarizing the mitochondrial membrane, as evidenced by a TMRE assay. Further analysis using the molecular fluorescent probe H2DCFDA indicated that the increased levels of reactive oxygen species (ROS) might be linked to altered mitochondrial membrane potential and cell death. Furthermore, viable cells were observed to be delayed in the cell cycle, primarily in the M phase, and the invasion process was reduced. The findings of this study indicate that Q1VA is a potential adjuvant therapeutic agent for GBM due to its significant antitumor effects. If its safety and efficacy can be confirmed in animal models, Q1VA may be considered for clinical trials in humans. However, additional research is required to determine the optimal dosage, treatment schedule, and potential side effects of Q1VA.
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Open AccessReview
Convergence of Pro-Stress and Pro-Inflammatory Signaling in the Central Noradrenergic System: Implications for Mood and Anxiety Disorders
by
Arthur Anthony A. Reyes and Daniel J. Chandler
Neuroglia 2023, 4(2), 87-101; https://doi.org/10.3390/neuroglia4020007 - 29 Apr 2023
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Mood and anxiety disorders are heterogeneous psychiatric diagnoses affecting millions. While the disease etiology is complex, various risk factors have been identified, such as stress. Stress is a neuroendocrine physiologic response to a stressor that promotes organism survival through adaptive processes and behavior.
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Mood and anxiety disorders are heterogeneous psychiatric diagnoses affecting millions. While the disease etiology is complex, various risk factors have been identified, such as stress. Stress is a neuroendocrine physiologic response to a stressor that promotes organism survival through adaptive processes and behavior. The central stress response, which drives behavioral and physiological change, is primarily mediated by activating the hypothalamic–pituitary–adrenal (HPA) axis. In addition to its effects on the HPA axis, stress activates the locus coeruleus (LC), a bilateral brainstem nucleus that projects broadly throughout the central nervous system and releases the catecholamine transmitter norepinephrine (NE). The combined activities of the LC–NE system and HPA axis work synergistically to produce timely adaptive physiological and behavioral responses to stress. While advantageous in the short term, chronic stress exposure can lead to HPA axis and LC dysregulation, which are thought to contribute to the etiology of several neuropsychiatric disease states. Notably, recent studies have also implicated neuroinflammation mediated by microglia as a risk factor in mood and anxiety disorders. Despite their combined association with mood and anxiety disorders, the potential links between stress and inflammation, and possible interactions between their respective signaling cascades, have not been well-explored. This brief review aims to summarize how LC is uniquely positioned to respond to both pro-stress and pro-inflammatory cues, and how their convergence in this site may contribute to the development of mood and anxiety disorders.
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Open AccessArticle
Targeting Bioinformatics Predicted Biomarkers Associated with Cell Proliferation and Migration for Treating Gliomas: Preclinical Studies in a GL261 Mouse Model
by
Rheal A. Towner, Nataliya Smith, Debra Saunders, Megan Lerner, Randy L. Jensen, James Battiste, Marya Ahmed and Jonathan D. Wren
Neuroglia 2023, 4(1), 69-86; https://doi.org/10.3390/neuroglia4010006 - 15 Mar 2023
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We previously reported on the experimental validation of several in silico-predicted glioma biomarkers (e.g., Plexin-B2 (PLXNB2), SLIT3, and Spondin-1 (SPON1)) that were found to be higher in human high-grade gliomas (HGGs). In this study, we validated their therapeutic potential by investigating antibody therapies
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We previously reported on the experimental validation of several in silico-predicted glioma biomarkers (e.g., Plexin-B2 (PLXNB2), SLIT3, and Spondin-1 (SPON1)) that were found to be higher in human high-grade gliomas (HGGs). In this study, we validated their therapeutic potential by investigating antibody therapies against these three biomarkers in a preclinical mouse GL261 high-grade glioma model. Efficacies for antibody therapies against these biomarkers were assessed by survival and tumor volumes, biomarker expressions, cell invasion and proliferation, and bioinformatics gene/protein associations. Antibodies against PLXNB2, SLIT3, or SPON1 were effective in significantly reducing tumor volumes and increasing animal survival. With immunohistochemistry (IHC), these biomarkers were highly expressed in human HGGs, as well as in mice tumors. From IHC, CD44v6 was significantly decreased for all three antibody treatments, compared to UT GL261 tumors. Bioinformatics suggested that targeting either PLXNB2 or SPON1 may have a major effect on HGG cell migration and invasion (validated with CD44v6 IHC), whereas targeting SLIT3, in addition to affecting cell invasion, may also affect cell proliferation (not validated with Ki67 IHC). These results indicate that targeting these three biomarkers could add to the therapeutic arsenal against high-grade gliomas and that antibodies against them could be considered for clinical translation.
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Open AccessArticle
Modest Reduction in CAG Repeat Length Rescues Motor Deficits but Not Purkinje Cell Pathology and Gliosis in Spinocerebellar Ataxia Type 1 Mice
by
Stephen Gilliat, Juao-Guilherme Rosa, Genevieve Benjamin, Kaelin Sbrocco, Wensheng Lin and Marija Cvetanovic
Neuroglia 2023, 4(1), 52-68; https://doi.org/10.3390/neuroglia4010005 - 07 Mar 2023
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Spinocerebellar ataxia type 1 (SCA1) is a fatal, dominantly inherited neurodegenerative disease caused by the expansion of CAG repeats in the Ataxin-1 (ATXN1) gene. SCA1 is characterized by the early and prominent pathology of the cerebellar Purkinje cells that results in
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Spinocerebellar ataxia type 1 (SCA1) is a fatal, dominantly inherited neurodegenerative disease caused by the expansion of CAG repeats in the Ataxin-1 (ATXN1) gene. SCA1 is characterized by the early and prominent pathology of the cerebellar Purkinje cells that results in balance and coordination deficits. We previously demonstrated that cerebellar astrocytes contribute to SCA1 pathogenesis in a biphasic, stage of disease-dependent manner. We found that pro-inflammatory transcriptional regulator nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling in astrocytes has a neuroprotective role during early-stage SCA1. Here, we sought to examine whether further inducing NF-κB activation in astrocytes of SCA1 model mice at an early stage of the disease has therapeutic benefits. To perform this task, we created a novel Slc1a3-CreERT/IKKβCA/ATXN1[82Q] triple transgenic mouse model in which TMX injection at 4 weeks of age results in the expression of constitutively active inhibitor of kB kinase beta (IKKβCA), the main activator of NF-κB signaling. As we evaluated SCA1-like phenotypes, we noticed that ATXN1[82Q] mice did not exhibit motor deficits anymore, even at very late stages of the disease. We sequenced the mutant ATXN1 gene and discovered that the CAG repeat number had decreased from 82 to 71. However, despite the loss of motor phenotype, other well-characterized SCA1-changes, including atrophy of Purkinje cell dendrites, hallmarks of cerebellar astrogliosis and microgliosis, and Purkinje cell disease-associated gene expression changes, were still detectable in ATXN1[71Q] mice. We found delayed PC atrophy and calbindin reduction in SCA1 mice expressing IKKβCA in astrocytes implicating beneficial effects of increased NF-κB signaling on Purkinje cell pathology. The change in the motor phenotype of SCA1 mice with CAG reduction prevented us from evaluating the neuroprotective potential of IKKβCA on motor deficits in these mice.
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