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Role of Glia in Human Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 January 2026) | Viewed by 17620

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Dr. Daniele Lana

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Department of Health Sciences, University of Florence, 50134 Florence, Italy
Interests: neuropharmacology; neurodegeneration; neuroinflammation; glia; microbiota; neurodegenerative diseases; hippocampus; behaviour
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Hajime Hirase

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1. Center for Translational Neuromedicine, Faculty of Medical and Health Sciences, University of Copenhagen, 1172 Copenhagen, Denmark
2. Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
Interests: astrocytic signaling; neural circuit; behavioral performance

Special Issue Information

Dear Colleagues,

The majority of brain cells are glia, and yet, over a century after their discovery, their real functions have still not been fully unraveled. Currently, our understanding of the role of glia in central nervous system (CNS) physiology and in neurodevelopmental, neurodegenerative, and demyelinating pathology is rapidly progressing. Glia, with their multiple functions, maintain the homeostasis of the CNS. Astrocytes are the most numerous and ubiquitous glial cells in the CNS and have many housekeeping functions; they bind the grey matter and enwrap synapses, maintain ion and neurotransmitter homeostasis, and regulate synaptogenesis. Microglia, the primary immune cells of the central nervous system, dynamically and continuously survey brain parenchyma to detect and eliminate debris from damaged neurons via phagocytosis and participate in shaping synaptic connectivity in the developing brain. Oligodendrocytes and Schwann cells myelinate axons, shaping the connectome.

Glia are vital, as their interactions with neurons determine the operation of the brain in health and disease states. These interactions form the basis of networks that show morphological and functional reciprocal reliance and dependency.

Alterations affecting one cell population reverberate and affect the others, favoring or dysregulating their activities. Glial cell phenomic dysfunction, whether in the form of atrophy with loss of function or reactivity, is associated with brain diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and glioblastoma, as well as autism and psychiatric disorders. Understanding the roles of glia will allow us to assess how their interactions can influence the state and progression of diseases and will be critical in identifying therapeutic strategies.

This Special Issue will comprise an in-depth analysis of how different types of glia participate in the physiological and pathological mechanisms behind CNS function and contribute to the onset or progression of brain diseases. In this regard, investigators are invited to contribute original research articles and reviews to improve our understanding of the role of glia in health and disease.

Dr. Daniele Lana
Prof. Dr. Hajime Hirase
Guest Editors

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Keywords

astrocytes
microglia
oligodendrocytes
Schwann cells
neurodegeneration

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Published Papers (11 papers)

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Research

Jump to: Review

22 pages, 6641 KB

Open AccessArticle

Alzheimer’s Spinal Pathology: Neuronal, Glial, and Cholesterol Metabolic Changes in Female and Male 5xFAD Mice

by Xiaochuan Wang, William Harnett, Xinhua Shu and Hui-Rong Jiang

Int. J. Mol. Sci. 2026, 27(8), 3593; https://doi.org/10.3390/ijms27083593 - 17 Apr 2026

Viewed by 307

Abstract

Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal aggregation of β-amyloid (Aβ) peptides, tau proteins, and neuroinflammation in the central nervous system (CNS). While most AD research has focused on the brain, the molecular pathology of the spinal cord remains poorly understood. In this study, we investigated amyloid pathology, neurodegeneration, neuroinflammation, and cholesterol metabolism across distinct regions of the spinal cord and examined sex-specific differences using a model of AD, 5xFAD mice. Our data reveal that Aβ accumulation was restricted to the cervical spinal cord at 3 months but was evident in all areas of the spinal cord by 9 months, with similar patterns in both female and male animals. Despite this early and progressive Aβ deposition, no significant neuronal loss was observed in the ventral horn of the cervical spinal cord in either sex at 3 or 9 months of age. In contrast, there was a significant positive correlation between Aβ deposition and Iba1+ cell density in the spinal cord of 5xFAD mice. The number of Iba1+ cells in both the grey and white matter was significantly increased in female and male 5xFAD mice compared with age-matched wild-type (WT) littermates at 9 months of age. Astrocytic responses, however, were sex-specific: female, but not male, 5xFAD mice exhibited a significant increase in GFAP+ astrocytes in the grey matter of the thoracic and lumber spinal cord at 9 months compared with 3 months and relative to age-matched WT controls in the cervical and thoracic spinal cord. Furthermore, GFAP+ area in the thoracic spinal cord was significantly higher in female 9-month-old 5xFAD mice compared with their male counterparts, indicating a female-specific astrocytic response in AD spinal cord pathology. Our data also show an increase in free cholesterol (Filipin+ area) in 5xFAD mice at 9 months relative to WT controls, accompanied by altered expression of cholesterol metabolism genes, including downregulation of Abca1, Cyp46a1 and Cyp27a1. Collectively, these findings provide new insights into AD progression in the spinal cord, highlighting molecular pathology of AD extending beyond the brain. Full article

(This article belongs to the Special Issue Role of Glia in Human Health and Disease)

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19 pages, 3404 KB

Open AccessArticle

State-Dependent Remodeling of Astrocytic Proteome and Phosphorylation Signaling Networks Across Wake, Sleep, and General Anesthesia

by Mengchan Su, Qingran Li, Ping Liao, Fan Lei, Xin Li, Liyun Deng, Juexi Yang, Fan Lu, Bin Zhou and Ruotian Jiang

Int. J. Mol. Sci. 2026, 27(5), 2159; https://doi.org/10.3390/ijms27052159 - 25 Feb 2026

Viewed by 560

Abstract

Astrocytes critically regulate states of consciousness, yet their molecular profiles across wake, sleep, and general anesthesia remain unclear. This study conducted proteomic and phosphoproteomic analyses of rat cortical astrocytes across these states using sevoflurane. Data quality was validated using principal component analysis (PCA) and Pearson correlation coefficient (PCC). Proteomics showed state-specific signatures: sleep and anesthesia shared similar changes (downregulated structural proteins, upregulated membrane transport complexes) but diverged in molecular expression. Anesthesia specifically suggested potential activation of cellular differentiation/structural plasticity-related pathways but implied potential disruption of metabolism and molecular clearance processes compared to sleep. Phosphoproteomics revealed the unique phosphorylation changes during general anesthesia compared to wake and normal sleep: downregulated phosphorylation of nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) at Ser188, suggesting the potential suppression of nuclear transcription and/or cell cycle activity, which may act as a potential molecular signature associated with the anesthetic state. Clustering analysis showed that sleep was associated with upregulated mRNA processing, while anesthesia indicated potential enhancement of synaptic signaling and suggested possible suppression of development-related programs. In summary, astrocytes undergo extensive molecular reprogramming during transitions of consciousness; while they share common features in morphological remodeling, sleep and anesthesia differ fundamentally in astrocytic molecular outcomes, offering new insights into astrocytic roles in unconsciousness. Full article

(This article belongs to the Special Issue Role of Glia in Human Health and Disease)

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16 pages, 865 KB

Open AccessArticle

LRRC8-Mediated Glutamate Release from Astrocytes Is Not Increased During the Initiation of Experimental Temporal Lobe Epilepsy

by Kamyab Sarmadi, Linda Gaspar, Peter Bedner, Lukas Henning, Christian Henneberger, Ronald Jabs, Thomas J. Jentsch, Christian Steinhäuser and Gerald Seifert

Int. J. Mol. Sci. 2026, 27(3), 1589; https://doi.org/10.3390/ijms27031589 - 5 Feb 2026

Viewed by 607

Abstract

LRRC8 channels are volume-regulated anion channels (VRACs) activated by cellular swelling, which mediate regulatory volume decrease in many cell types. Recently, it has been shown that these channels contribute to the release of glutamate from astrocytes. Since enhanced extracellular glutamate concentrations produce hyperexcitability, and microdialysis revealed elevated levels of the transmitter in the brains of epileptic patients, we asked whether astroglial glutamate release through LRRC8/VRACs might contribute to the initiation of experimental temporal lobe epilepsy (TLE). Patch clamp, pharmacological, and single-cell transcript analyses were performed in the hippocampus of controls and mice with inducible deletion of LRRC8a in astrocytes. In addition, these mice were exposed to our unilateral intracortical kainate model of TLE. Tonic currents were recorded from CA1 pyramidal neurons as a measure of glutamate release. Our data show that neither expression of LRRC8a nor the amplitude of tonic currents was altered 4 h after status epilepticus-induced TLE. These findings do not suggest that increased astroglial glutamate release through LRRC8 channels contributes to the initiation of experimental TLE. Full article

(This article belongs to the Special Issue Role of Glia in Human Health and Disease)

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23 pages, 3507 KB

Open AccessArticle

Dynamic Behavioral and Molecular Changes Induced by Chronic Restraint Stress Exposure in Mice

by Thomas D. Prevot, Jaime K. Knoch, Dipashree Chatterjee, Sierra Codeluppi-Arrowsmith, Keith A. Misquitta, Corey J. E. Fee, Dwight Newton, Hyunjung Oh, Etienne Sibille and Mounira Banasr

Int. J. Mol. Sci. 2026, 27(1), 167; https://doi.org/10.3390/ijms27010167 - 23 Dec 2025

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Abstract

Chronic stress is a major risk factor contributing to cellular changes in the brain that precipitate the emergence of various behavioral changes, including anxiety and anhedonia—symptoms relevant to mood disorders including major depression—however the sequence and trajectory of early molecular changes is poorly characterized. Using the chronic restraint stress (CRS) model in mice (N = 6–8/sex/group), we assessed the impact of 0, 7, 14, 21, 28, or 35 days of CRS at the behavioral level on the emergence of anxiety-like and anhedonia-like phenotypes. While 7 days of CRS was sufficient to induce anxiety-like behaviors in the PhenoTyper test, anhedonia-like deficits in the sucrose consumption test were only observed after 35 days of CRS. We also investigated the underlying molecular changes in the prefrontal cortex, a limbic brain region highly sensitive to stress, using Western blot and qPCR. We found that protein or RNA levels of several markers known to be implicated in the pathology of depression, and markers of synapses (post synaptic density protein 95 (PSD95), synapsin-1 (SYN1), vesicular glutamate transporter-1 (VGLUT1), and gephyrin (GPHN)); GABAergic inhibitory interneurons (somatostatin (SST), parvalbumin (PV), glutamic acid decarboxylase-67 (GAD67), and vasoactive intestinal peptide (VIP)); and astroglia (glial fibrillary acidic protein (GFAP), glutamate transporter-1 (GLT1), and glutamine synthase (GS)) were gradually reduced by CRS. Interestingly, all three astroglial markers were negatively correlated with anhedonia-like behaviors, while SYN1 and GPHN negatively correlated with anxiety-like behaviors. GLT1, VGLUT1, SYN1, and GAD67 negatively correlated with Z-emotionality scores. Exploratory between-marker correlations and integrative network analyses revealed that CRS effects might be driven by different compartments (synaptic, GABAergic and astroglial) depending on sex. Our study demonstrates that CRS induces dynamic changes that can be observed at the behavioral and molecular levels, and that male and female mice, while exhibiting similar symptoms, may experience different underlying pathologies. Full article

(This article belongs to the Special Issue Role of Glia in Human Health and Disease)

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20 pages, 1382 KB

Open AccessArticle

Glia Cells Are Selectively Sensitive to Nanosized Titanium Dioxide Mineral Forms

by Eszter Geiszelhardt, Erika Tóth, Károly Bóka, Norbert Bencsik, Katalin Schlett and Krisztián Tárnok

Int. J. Mol. Sci. 2025, 26(19), 9684; https://doi.org/10.3390/ijms26199684 - 4 Oct 2025

Viewed by 936

Abstract

Nanosized titanium dioxide is widely used by the industry, e.g., in pigments, suncreams, and food colors. Its environmental and biological effects have been investigated in the past; however, few studiesd have focused on its crystal structure-specific effects. In our experiments, the toxicity of two types of synthetic nanoparticles was examined on primary neural cultures with different cell compositions using MTT and LDH assays. Primary murine cell cultures containing only astroglia cells originated from two brain regions, as well as mixed neurons and glia cells or microglia cells exclusively, were treated with anatase (15.8 ± 1.7 nm average diameter) and rutile (46.7 ± 2.2 nm average length and 13.7 ± 0.7 nm average diameter) TiO₂ nanoparticles at varying concentrations for 24 or 48 h. Our results show that neither anatase nor rutile nanoparticles reduced viability in cell cultures containing a mixture of neurons and glial cells, independently of the applied concentration and treatment time. Rutile but not anatase form induced cell death in cortical astroglia cultures already at 24 h of treatment above 10 µg/mL, while hippocampus-derived glial cultures were much less sensitive to rutile. The rutile form also damaged microglia. These findings suggest that products containing rutile-form nano-titanium particles may pose a targeted risk to astroglia and microglial cells in the central nervous system. Full article

(This article belongs to the Special Issue Role of Glia in Human Health and Disease)

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33 pages, 8117 KB

Open AccessArticle

Induced Microglial-like Cells Derived from Familial and Sporadic Alzheimer’s Disease Peripheral Blood Monocytes Show Abnormal Phagocytosis and Inflammatory Response to PSEN1 E280A Cholinergic-like Neurons

by Viviana Soto-Mercado, Miguel Mendivil-Perez, Carlos Velez-Pardo and Marlene Jimenez-Del-Rio

Int. J. Mol. Sci. 2025, 26(15), 7162; https://doi.org/10.3390/ijms26157162 - 24 Jul 2025

Cited by 1 | Viewed by 2160

Abstract

In familial Alzheimer’s disease (FAD), presenilin 1 (PSEN1) E280A cholinergic-like neurons (ChLNs) induce aberrant secretion of extracellular amyloid beta (eAβ). How PSEN1 E280A ChLNs-eAβ affects microglial activity is still unknown. We obtained induced microglia-like cells (iMG) from human peripheral blood cells (hPBCs) in a 15-day differentiation process to investigate the effect of bolus addition of Aβ42, PSEN1 E280A cholinergic-like neuron (ChLN)-derived culture supernatants, and PSEN1 E280A ChLNs on wild type (WT) iMG, PSEN1 E280A iMG, and sporadic Alzheimer’s disease (SAD) iMG. We found that WT iMG cells, when challenged with non-cellular (e.g., lipopolysaccharide, LPS) or cellular (e.g., Aβ42, PSEN1 E280A ChLN-derived culture supernatants) microenvironments, closely resemble primary human microglia in terms of morphology (resembling an “amoeboid-like phenotype”), expression of surface markers (Ionized calcium-binding adapter molecule 1, IBA-1; transmembrane protein 119, TMEM119), phagocytic ability (high pHrodo™ Red E. coli BioParticles™ phagocytic activity), immune metabolism (i.e., high generation of reactive oxygen species, ROS), increase in mitochondrial membrane potential (ΔΨm), response to ATP-induced transient intracellular Ca²⁺ influx, cell polarization (cluster of differentiation 68 (CD68)/CD206 ratio: M1 phenotype), cell migration activity according to the scratch wound assay, and especially in their inflammatory response (secretion of cytokine interleukin-6, IL-6; Tumor necrosis factor alpha, TNF-α). We also found that PSEN1 E280A and SAD iMG are physiologically unresponsive to ATP-induced Ca²⁺ influx, have reduced phagocytic activity, and diminished expression of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) protein, but when co-cultured with PSEN1 E280A ChLNs, iMG shows an increase in pro-inflammatory phenotype (M1) and secretes high levels of cytokines IL-6 and TNF-α. As a result, PSEN1 E280A and SAD iMG induce apoptosis in PSEN1 E280A ChLNs as evidenced by abnormal phosphorylation of protein TAU at residue T205 and cleaved caspase 3 (CC3). Taken together, these results suggest that PSEN1 E280A ChLNs initiate a vicious cycle between damaged neurons and M1 phenotype microglia, resulting in excessive ChLN death. Our findings provide a suitable platform for the exploration of novel therapeutic approaches for the fight against FAD. Full article

(This article belongs to the Special Issue Role of Glia in Human Health and Disease)

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17 pages, 9996 KB

Open AccessArticle

Activity of Human-Specific Interlaminar Astrocytes in a Chimeric Mouse Model of Fragile X Syndrome

by Alexandria Anding, Baiyan Ren, Ragunathan Padmashri, Maria Burkovetskaya and Anna Dunaevsky

Int. J. Mol. Sci. 2025, 26(13), 6510; https://doi.org/10.3390/ijms26136510 - 6 Jul 2025

Cited by 3 | Viewed by 1404

Abstract

Astrocytes, a subtype of glial cells, have multiple roles in regulating neuronal development and homeostasis. In addition to the typical mammalian astrocytes, in the primate cortex, interlaminar astrocytes are located in the superficial layer and project long processes traversing multiple layers of the cerebral cortex. Previously, we described a human stem cell based chimeric mouse model where interlaminar astrocytes develop. Here, we utilized this model to study the calcium signaling properties of interlaminar astrocytes. To determine how interlaminar astrocytes could contribute to neurodevelopmental disorders, we generated a chimeric mouse model for Fragile X syndrome (FXS). We report that FXS interlaminar astrocytes exhibit hyperexcitable calcium signaling and are associated with dendritic spines with increased turnover rate. Full article

(This article belongs to the Special Issue Role of Glia in Human Health and Disease)

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21 pages, 6059 KB

Open AccessArticle

Chronic Chemogenetic Activation of Astrocytes in the Murine Mesopontine Region Leads to Disturbances in Circadian Activity and Movement

by Baneen Maamrah, Krisztina Pocsai, Bui Minh Hoang, Ali Abdelhadi, Mustafa Qais Al-Khafaji, Andrea Csemer, Cintia Sokvári, Péter Szentesi and Balázs Pál

Int. J. Mol. Sci. 2025, 26(10), 4793; https://doi.org/10.3390/ijms26104793 - 16 May 2025

Viewed by 1270

Abstract

We have previously shown that neuromodulatory actions on astrocytes can elicit metabotropic glutamate- and N-methyl-D-aspartate receptor-dependent tonic changes in excitability in the mesopontine region. Although in vitro experiments explored robust effects, the in vivo significance of our findings remained unknown. In this project, chronic chemogenetic activation of mesopontine astrocytes and its actions on movement, circadian activity, acoustic startle and spatial memory were tested. The control group of young adult male mice where mesopontine astrocytes expressed only the mCherry fluorescent tag was compared to the group expressing the hM3D(Gq) chemogenetic actuator. Chronic chemogenetic astrocyte activation reduced the amplitude of the acoustic startle reflex and increased the locomotion speed in the resting period. Gait alterations were also demonstrated but no change in the spatial memory was explored. As a potential background of these findings, chronic astrocytic activation decreased the cholinergic neuronal number to 54% and reduced the non-cholinergic neuronal number to 76% of the control. In conclusion, chronic astrocytic activation and the consequential decrease in the neuronal number led to disturbances in movement and circadian activity resembling brainstem-related symptoms of progressive supranuclear palsy, raising the possibility that astrocytic overactivation is involved in the pathogenesis of this disease. Full article

(This article belongs to the Special Issue Role of Glia in Human Health and Disease)

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Review

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37 pages, 668 KB

Open AccessReview

Pharmacological Therapies for Consequences of Perinatal Hypoxic-Ischemic Brain Injury: Where Are We Now?

by Paulina Gebala, Justyna Janowska and Joanna Sypecka

Int. J. Mol. Sci. 2025, 26(20), 10200; https://doi.org/10.3390/ijms262010200 - 20 Oct 2025

Cited by 1 | Viewed by 2695

Abstract

Despite significant progress in preclinical research aimed at developing effective therapies for the acute and long-term consequences of perinatal asphyxia, there is still a lack of clinical protocols to regenerate the neonatal brain damaged by hypoxic-ischemic (HI) injury. To date, only therapeutic hypothermia is routinely used in neonates who have experienced perinatal asphyxia. It has been shown to be effective only in limiting the spread of brain damage caused by a cascade of molecular and biochemical events triggered by limited blood supply to the body’s organs, including the fragile, developing brain. Ongoing clinical trials are exploring pharmacological approaches aimed at promoting neurogenesis and gliogenesis to repair damaged neural tissue, as well as modulating the neuroinflammation that results from the cellular response to HI injury. Among promising therapeutic agents, erythropoietin, and melatonin have emerged as major drugs with potential neuroprotective effects in neonatal hypoxic-ischemic encephalopathy. Erythropoietin is recognized for its anti-apoptotic, anti-oxidative, and anti-inflammatory properties, supporting neural cell survival and regeneration. Melatonin acts as a potent antioxidant and anti-inflammatory agent, helping to reduce oxidative stress and inflammation triggered by HI injury. As clinical trials on suffering neonates are highly demanding, the ethical and practical concerns of therapeutic approaches are discussed. An urgent need to develop a safe, feasible, and effective clinical approach to promote the restoration of appropriate neurodevelopment in the near future is highlighted. This review summarizes the clinical trials conducted to date, discusses their outcomes and limitations, and considers translational potential of the tested treatment strategies. Full article

(This article belongs to the Special Issue Role of Glia in Human Health and Disease)

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16 pages, 636 KB

Open AccessReview

Stress-Induced Membraneless Organelles in Neurons: Bridging Liquid–Liquid Phase Separation and Neurodevelopmental Dysfunction

by Norbert Bencsik, Daniel Kimsanaliev, Krisztián Tárnok and Katalin Schlett

Int. J. Mol. Sci. 2025, 26(18), 9068; https://doi.org/10.3390/ijms26189068 - 17 Sep 2025

Cited by 1 | Viewed by 2862

Abstract

Liquid–liquid phase separation (LLPS) in cell biology has revolutionized our understanding of how cells organize biochemical reactions and structures through dynamic, membraneless organelles (MLOs). In neurons, LLPS-driven processes are particularly important for regulating synaptic plasticity, RNA metabolism, and responses to environmental stressors. Over the past decade, LLPS has gained increasing attention in neurobiology as a framework to interpret altered synaptic functions in various neurodevelopmental disorders (NDDs). These diseases comprise a diverse spectrum of clinical and pathological symptoms (e.g., global developmental delay, impaired cognitive and mental functions, as well as social withdrawal). Recent studies have highlighted how mutations in proteins containing intrinsically disordered regions (IDRs)—key drivers of LLPS—can alter condensate properties, resulting in persistent or defective MLO formation. These aberrant assemblies may disrupt RNA transport, splicing, and translation in developing neurons, thereby contributing to disorder pathology. IDRs are known to be enriched in membraneless components, such as stress granules, nuclear paraspeckles, and P-bodies, where they play crucial role in the formation, maintenance, and function of protein–RNA networks. This review explores the role of stress-induced MLOs in the nervous system, the molecular principles governing their formation, and how their dysfunction bridges the gap between environmental stress responses and neurodevelopmental impairment. Full article

(This article belongs to the Special Issue Role of Glia in Human Health and Disease)

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19 pages, 1743 KB

Open AccessReview

Dynamic Intercellular Networks in the CNS: Mechanisms of Crosstalk from Homeostasis to Neurodegeneration

by Yutian Zheng, Rui Huang and Jie Pan

Int. J. Mol. Sci. 2025, 26(17), 8155; https://doi.org/10.3390/ijms26178155 - 22 Aug 2025

Cited by 5 | Viewed by 2477

Abstract

Intercellular communication in the central nervous system (CNS) is essential for maintaining neural function and coordinating responses to injury or disease. With recent advances in single-cell and spatial transcriptomics, a growing body of research has revealed that this communication is highly dynamic, shifting across states of health, aging, demyelination, and neurodegeneration. In this review, we synthesize the current findings on intercellular communication networks involving neurons, astrocytes, microglia, oligodendrocytes, and other glial populations in the CNS across four major states: healthy homeostasis, aging, demyelinating diseases, and Alzheimer’s disease (AD). We focus on how changes in intercellular communication contribute to the maintenance or disruption of CNS integrity and function. Mechanistic insights into these signaling networks have revealed new molecular targets and pathways that may be exploited for therapeutic intervention. By comparing the intercellular signaling mechanisms across different disease contexts, we underscore the importance of CNS crosstalk not only as a hallmark of disease progression, but also as a potential gateway for precision therapy. Full article

(This article belongs to the Special Issue Role of Glia in Human Health and Disease)

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