Search Results (819)

In recent decades, substantial evidence has highlighted the integral roles of neuroglia, particularly astrocytes, microglia, oligodendrocytes, and ependymal cells, in the regulation of synaptic transmission, metabolic support, and immune mechanisms within the central nervous system. In addition to their structural role, these cells actively modulate neurotransmitter homeostasis and influence neuronal plasticity, thereby affecting cognition, mood, and behavior. This review discusses how neuroglial alterations contribute to the pathophysiology of five common psychiatric disorders: major depression, bipolar disorder, anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and schizophrenia. We synthesized preclinical and clinical findings illustrating that glial dysfunction, including impaired myelination and aberrant neuroinflammatory responses, often parallels disease onset and severity. Moreover, we outline how disruptions in astrocytic glutamate uptake, microglia-mediated synaptic pruning, and blood–brain barrier integrity may underlie the neurobiological heterogeneity observed in these disorders. The therapeutic implications range from anti-inflammatory agents to investigational compounds that aim to stabilize glial function or promote remyelination. However, challenges due to interindividual variability, insufficient biomarkers, and the multifactorial nature of psychiatric illnesses remain. Advances in neuroimaging, liquid biopsy, and more precise molecular techniques may facilitate targeted interventions by stratifying patient subgroups with distinct glial phenotypes. Continued research is essential to translate these insights into clinically efficacious and safe treatments. Full article

Spinal cord injury (SCI) is a life-altering condition that leads to severe neurological deficits and significantly impacts patients’ quality of life. Despite advancements in medical care, current treatment options remain largely palliative, with limited ability to promote meaningful functional recovery. Induced pluripotent stem cells (iPSCs) have emerged as a promising avenue for regenerative medicine, offering patient-specific, cell-based therapeutic potential for SCI repair. This review provides a comprehensive overview of recent advancements in iPSC-based approaches for SCI, detailing the strategies used to generate neural cell types, including neural progenitor cells, oligodendrocytes, astrocytes, and microglia, and their roles in promoting neuroprotection and regeneration. Additionally, we examine key preclinical and clinical studies, highlighting functional recovery assessments and discussing both standardized and debated evaluation metrics. Furthermore, we address critical challenges related to safety, tumorigenicity, immune response, survival, integration, and overcoming the inhibitory microenvironment of the injured spinal cord. We also explore emerging approaches in biomaterial scaffolds, gene editing, and rehabilitation strategies that may enhance the clinical applicability of iPSC-based therapies. By addressing these challenges and refining translational strategies, iPSC-based interventions hold significant potential to revolutionize SCI treatment and improve outcomes for affected individuals. Full article

Despite improved neonatal intensive care, the risk of premature-born infants developing bronchopulmonary dysplasia (BPD) and encephalopathy of prematurity (EoP) remains high. With hyperoxia being a major underlying factor, both preterm-birth-related complications are suggested to be closely interrelated. However, experimental models are lacking for the assessment of the potentially close interplay between both organs. To establish a model, suitable for the assessment of both affected organs, Wistar rats were exposed to 80% oxygen from postnatal day 2 (P2) for seven days. Brain and lung tissues were analysed via histomorphometry, immunohistochemistry, real-time PCR, and western blot at term P11. In the brain, hyperoxia induced significant hypomyelination accompanied by a reduction in oligodendrocytes and CD68 expression on microglia cells. These changes correlate with arrested alveolarisation and an increased number of macrophages in the lung. Interestingly, in contrast to the reduced formation of pulmonary microvessels, an increased vascular density was detected in the brain. Seven days of hyperoxia induces typical characteristics of BPD and EoP in neonatal rats, thereby linking impaired alveolarisation with disturbed myelination in the brain and providing an experimental model for understanding pathophysiological mechanisms and identifying organ-spanning novel therapeutic interventions targeting both diseases. Full article

Background: Alcohol-related brain damage (ARBD) causes cognitive-behavioral impairments that can lead to dementia. White matter is a major target in ARBD. Additional research is needed to better understand the mechanisms of ARBD progression to advanced stages with permanent disability. Potential contributing factors include neuroinflammation and altered signaling through pathways that regulate cell survival, neuronal plasticity, myelin maintenance, and energy metabolism. Objectives: This study characterizes the time course-related effects of chronic heavy ethanol feeding on white matter myelin protein expression, neuroinflammation, and molecules that mediate signaling through the mechanistic target of rapamycin (mTOR) pathways. Methods: Adult Long Evans rats (8–12/group) were fed with isocaloric liquid diets containing 0% (control) or 36% ethanol. Experimental endpoints spanned from 1 day to 8 weeks. The frontal lobes were used for histopathology and molecular and biochemical analyses. Results: Chronic ethanol feeding caused significant brain atrophy that was detected within 4 weeks and sustained over the course of the study. Early exposure time points, i.e., 2 weeks or less, were associated with global increases in the expression of non-myelinating, myelinating, and astrocyte markers, whereas at 6 or 8 weeks, white matter oligodendrocyte/myelin/glial protein expression was reduced. These effects were not associated with shifts in neuroinflammatory markers. Instead, the early stages of ARBD were accompanied by increases in several mTOR proteins and phosphoproteins, while later phases were marked by inhibition of downstream mTOR signaling through P70S6K. Conclusions: Short-term versus long-term ethanol exposures differentially altered white matter glial protein expression and signaling through mTOR’s downstream mediators that have known roles in myelin maintenance. These findings suggest that strategic targeting of mTOR signaling dysregulation may be critical for maintaining the functional integrity of white matter and ultimately preventing long-term ARBD-related cognitive impairment. Full article

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous deletions or mutations in the SMN1 gene, leading to progressive motor neuron degeneration. While SMA has been classically viewed as a motor neuron-autonomous disease, increasing evidence indicates a significant role of glial cells—astrocytes, microglia, oligodendrocytes, and Schwann cells—in the disease pathophysiology. Astrocytic dysfunction contributes to motor neuron vulnerability through impaired calcium homeostasis, disrupted synaptic integrity, and neurotrophic factor deficits. Microglia, through reactive gliosis and complement-mediated synaptic stripping, exacerbate neurodegeneration and neuroinflammation. Oligodendrocytes exhibit impaired differentiation and metabolic support, while Schwann cells display abnormalities in myelination, extracellular matrix composition, and neuromuscular junction maintenance, further compromising motor function. Dysregulation of pathways such as NF-κB, Notch, and JAK/STAT, alongside the upregulation of complement proteins and microRNAs, reinforces the non-cell-autonomous nature of SMA. Despite the advances in SMN-restorative therapies, they do not fully mitigate glial dysfunction. Targeting glial pathology, including modulation of reactive astrogliosis, microglial polarization, and myelination deficits, represents a critical avenue for therapeutic intervention. This review comprehensively examines the multifaceted roles of glial cells in SMA and highlights emerging glia-targeted strategies to enhance treatment efficacy and improve patient outcomes. Full article

Vestibular disorders significantly affect individuals by impairing balance, spatial orientation, and quality of life. Despite the focus on neuronal mechanisms, emerging research emphasizes the importance of neuroglia—astrocytes, microglia, oligodendrocytes, and Schwann cells—in the onset, progression, and resolution of these conditions. This narrative review explores the roles of neuroglia in vestibular disorders, including vestibular migraines and unilateral and bilateral vestibulopathies. It discusses established facts, challenges, and future perspectives, offering insights into their pathophysiological roles and therapeutic implications, and the limitations of current research. By understanding the interplay between neuroglia and vestibular function, this review aims to advance diagnostic and treatment strategies for these disorders Full article

Background/Objectives: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by challenges in social communication, restricted interests, and repetitive behaviors. Recent studies highlight the crucial roles of neuroglial cells—astrocytes, microglia, and oligodendrocytes—in synaptic function, neural connectivity, and neuroinflammation. These findings offer a fresh perspective on ASD pathophysiology. This review synthesizes current knowledge on neuroglial dysfunction in ASD, emphasizing its role in pathophysiological mechanisms, genetic influences, and potential therapeutic strategies. Methods: We conducted a comprehensive literature review, integrating insights from neuroscience, molecular biology, and clinical studies. Special focus was given to glial-mediated neuroinflammatory mechanisms, synaptic plasticity regulation, and the impact of genetic mutations on neuroglial signaling and homeostasis. Results: Neuroglial dysfunction in ASD is evident in abnormal synaptic pruning by microglia, impaired astrocytic glutamate regulation, and defective oligodendrocyte-driven myelination, which collectively disrupt neuronal architecture. Emerging therapies targeting these pathways, including anti-inflammatory drugs, microglial modulators, and cell-based approaches, show promise in alleviating key ASD symptoms. Additionally, advanced interventions such as gene editing and glial progenitor therapy present opportunities to correct underlying neuroglial dysfunction. Conclusions: This review establishes a comprehensive framework for understanding neuroglial contributions to ASD. By integrating insights from diverse disciplines, it enhances our understanding of ASD pathophysiology and paves the way for novel therapeutic strategies targeting neuroglial pathways. Full article

MOGAD is a demyelinating syndrome with the presence of antibodies against myelin oligodendrocyte glycoprotein, which is, next to multiple sclerosis and the neuromyelitis optica spectrum, one of the manifestations of the demyelinating process, more common in the pediatric population. MOGAD can take a variety of clinical forms: acute disseminated encephalomyelitis (ADEM), retrobulbar optic neuritis, often binocular (ON), transverse myelitis (TM), or NMOSD-like course (neuromyelitis optica spectrum disorders), less often encephalopathy. The course may be monophasic (40–50%) or polyphasic (50–60%), especially with persistently positive anti-MOG antibodies. Very rarely, the first manifestation of the disease, preceding the typical symptoms of MOGAD by 8 to 48 months, is focal seizures with secondary generalization, without typical demyelinating changes on MRI of the head. The paper presents a case of a 17-year-old patient whose first symptoms of MOGAD were focal epileptic seizures in the form of turning the head to the right with the elevation of the left upper limb and salivation. Seizures occurred after surgical excision of a tumor of the right adrenal gland (ganglioneuroblastoma). Then, despite a normal MRI of the head and the exclusion of onconeural antibodies in the serum and cerebrospinal fluid after intravenous treatment, a paraneoplastic syndrome was suspected. After intravenous steroid treatment and immunoglobulins, eight plasmapheresis treatments, and the initiation of antiepileptic treatment, the seizures disappeared, and no other neurological symptoms occurred for nine months. Only subsequent relapses of the disease with typical radiological and clinical picture (ADEM, MDEM, recurrent ON) allowed for proper diagnosis and treatment of the patient both during relapses and by initiating supportive treatment. The patient’s case allows us to analyze the multi-phase, clinically diverse course of MOGAD and, above all, indicates the need to expand the diagnosis of epilepsy towards demyelinating diseases: determination of anti-MOG and anti-AQP4 antibodies. Full article

Multiple sclerosis (MS) is an autoimmune disease that damages the myelin sheath around the central nervous system axons, leading to neurological dysfunction. Although the initial damage is driven by inflammation, hypoxia has been reported in several brain regions of MS patients, but the significance of this for prognosis and treatment remains unclear. Neuroinflammation can induce hypoxia, and hypoxia can induce and exacerbate neuroinflammation, forming a vicious cycle. Within MS lesions, demyelination is often followed by remyelination, which may restore neurological function. However, demyelinated axons are vulnerable to damage, which leads to the accumulation of the permanent neurological dysfunction typical in MS, with this vulnerability heightened during hypoxia. Clinically approved therapies for MS are immunomodulatory, which can reduce relapse frequency/severity, but there is a lack of pro-regenerative therapies for MS, for example promoting remyelination. All tissues have protective responses to hypoxia, which may be relevant to MS lesions, especially during remyelinating episodes. When oxygen levels are reduced in the brain, constitutively expressed hypoxia-inducible factors (HIF) are stabilised, upregulating hundreds of genes, including neuroprotective factors. Furthermore, astrocytes upregulate heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) in the early stage of MS. HB-EGF promotes protective mechanisms and induces oligodendrocyte and neuron differentiation and survival. This review article outlines the neuroinflammation and hypoxia cycle in MS pathology and identifies potential therapeutic targets to limit neurodegeneration and/or promote regeneration. Both HIF and HB-EGF signalling pathways induce endogenous protection mechanisms in the CNS, promoting neuroprotection and remyelination directly, but also indirectly by modulating the immune response in MS. Promoting such endogenous protective signalling pathways could be an effective therapy for MS patients. Full article

Under conditions of amino acid deficiency, mammalian cells activate a nutrient-sensing kinase known as general control nonderepressible 2 (GCN2). The activation of GCN2 results in the phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (eIF2α), which can be phosphorylated by three other three integrated stress response (ISR) kinases, reducing overall protein synthesis. GCN2 activation also promotes the translation of specific mRNAs, some of which encode transcription factors that enhance the transcription of genes involved in the synthesis, transport, and metabolism of amino acids to restore cellular homeostasis. The phosphorylation of eIF2α has been shown to protect oligodendrocytes, the cells responsible for producing myelin in the central nervous system during remyelination. Here, we explore the potential role of the kinase GCN2 in the myelination process. We challenged mice deficient in the GCN2-encoding gene with a pharmacological demyelinating stimulus (cuprizone) and evaluated the recovery of myelin as well as ISR activation through the levels of eIF2α phosphorylation. Our findings indicate that GCN2 controls the establishment of myelin by fine-tuning its abundance and morphology in the central nervous system. We also found that GCN2 is essential for remyelination. Surprisingly, we discovered that GCN2 is necessary to maintain eIF2α levels during remyelination. Full article

Multiple system atrophy (MSA) is a progressive neurodegenerative synucleinopathy. Differentiating MSA from other synucleinopathies, especially in the early stages, is challenging because of its overlapping symptoms with other forms of Parkinsonism. Thus, there is a pressing need to clarify the underlying biological mechanisms and identify specific biomarkers for MSA. The metabolic profile of cerebrospinal fluid (CSF) is known to be altered in MSA. To further investigate the biological mechanisms behind the metabolic changes, we created a network of altered CSF metabolites in patients with MSA and analysed these changes using bioinformatic software. Acknowledging the limitations of metabolomics, we incorporated proteomic data to improve the overall comprehensiveness of the study. Our in silico predictions showed elevated ROS, cytoplasmic inclusions, white matter demyelination, ataxia, and neurodegeneration, with ATP concentration, neurotransmitter release, and oligodendrocyte count predicted to be suppressed in MSA CSF samples. Machine learning and dimension reduction are important multi-omics approaches as they handle large amounts of data, identify patterns, and make predictions while reducing variance without information loss and generating easily visualised plots that help identify clusters, patterns, or outliers. Thus, integrated multiomics and machine learning approaches are essential for elucidating neurodegenerative mechanisms and identifying potential diagnostic biomarkers of MSA. Full article

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder marked by progressive cognitive decline and memory loss, impacting millions of people around the world. The apolipoprotein E4 (ApoE4) allele is the most prominent genetic risk factor for late-onset AD, dramatically increasing disease susceptibility and accelerating onset compared to its isoforms ApoE2 and ApoE3. ApoE4’s unique structure, which arises from single-amino-acid changes, profoundly alters its function. This review examines the critical interplay between ApoE4 and microglia—the brain’s resident immune cells—and how this relationship contributes to AD pathology. We explore the molecular mechanisms by which ApoE4 modulates microglial activity, promoting a pro-inflammatory state, impairing phagocytic function, and disrupting lipid metabolism. These changes diminish microglia’s ability to clear amyloid-beta peptides, exacerbating neuroinflammation and leading to neuronal damage and synaptic dysfunction. Additionally, ApoE4 adversely affects other glial cells, such as astrocytes and oligodendrocytes, further compromising neuronal support and myelination. Understanding the ApoE4–microglia axis provides valuable insights into AD progression and reveals potential therapeutic targets. We discuss current strategies to modulate ApoE4 function using small molecules, antisense oligonucleotides, and gene editing technologies. Immunotherapies targeting amyloid-beta and ApoE4, along with neuroprotective approaches to enhance neuronal survival, are also examined. Future directions highlight the importance of personalized medicine based on individual ApoE genotypes, early biomarker identification for risk assessment, and investigating ApoE4’s role in other neurodegenerative diseases. This review emphasizes the intricate connection between ApoE4 and microglial dysfunction, highlighting the necessity of targeting this pathway to develop effective interventions. Advancing our understanding in this area holds promise for mitigating AD progression and improving outcomes for those affected by this relentless disease. Full article

Aneurysmal subarachnoid hemorrhage (SAH) involves a significant influx of blood into the cerebrospinal fluid, representing a severe form of stroke. Despite advancements in aneurysm closure and neuro-intensive care, outcomes remain impaired due to cerebral vasospasm and delayed cerebral ischemia (DCI). Previous pharmacological therapies have not successfully reduced DCI while improving overall outcomes. As a result, significant efforts are underway to better understand the cellular and molecular mechanisms involved. This review focuses on the activation and effects of immune cells after SAH and their interactions with neurotoxic and vasoactive substances as well as inflammatory mediators. Particular attention is given to clinical studies highlighting the roles of natural killer (NK) cells and regulatory T cells (Treg) cells. Alongside microglia, astrocytes, and oligodendrocytes, NK cells and Treg cells are key contributors to the inflammatory cascade following SAH. Their involvement in modulating the neuro-inflammatory response, vasospasm, and DCI underscores their potential as therapeutic targets and prognostic markers in the post-SAH recovery process. We conducted a systematic review on T cell- and natural killer cell-mediated inflammation and their roles in cerebral vasospasm and delayed cerebral ischemia. We conducted a meta-analysis to evaluate outcomes and mortality in studies focused on NK cell- and T cell-mediated mechanisms. Full article

Background/Objectives: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-related neurological disease that primarily affects the optic nerve and spinal cord. According to current international consensus guidelines for NMOSD, confirming the presence of aquaporin-4 immunoglobulin G antibody (AQP4-IgG) is one of the most important diagnostic criteria because AQP4-IgG is a significant diagnostic biomarker of NMOSD. Several assays are currently available for detecting AQP4-IgG, including cell-based assays (CBAs) and enzyme-linked immunosorbent assays (ELISAs). However, each assay has certain disadvantages, including insufficient sensitivity and specificity, the need for sophisticated techniques, and semi-quantitative results. Methods: We developed a fully automated chemiluminescent enzyme immunoassay (CLEIA) to detect AQP4-IgG (AQP4-CLEIA). This assay utilizes the recombinant antigen purified from the newly generated AQP4-M23 stably expressing Chinese hamster ovary cell line and an anti-AQP4 monoclonal antibody as a calibrator. Results: In analytical performance studies, the assay demonstrates good precision and linearity over the entire measurement range. Moreover, this assay showed no high-dose hook effect and interference from endogenous substances. In clinical validation studies, patients with AQP4-IgG positive NMOSD, multiple sclerosis, or myelin oligodendrocyte glycoprotein antibody-associated disorder and healthy individuals were tested. A cutoff value of 10.0 U/mL was determined by receiver operating characteristic curves based on the results of a microscopic live CBA. The sensitivity and specificity for AQP4-IgG-positive NMOSD were 97.0% and 100.0%, respectively, at the cutoff value. Conclusions: The results suggest that AQP4-CLEIA is a convenient automated method for measuring AQP4-IgG titers in hospitals and clinical laboratories, offering an effective alternative to the gold-standard CBA. Full article

Our recent study revealed that continuous prenatal low-dose-rate irradiation did not induce cellular changes in the dentate gyrus of the hippocampus in male B6C3F1 mice exposed to gamma rays during prenatal development. However, changes in body weight, body mass index (BMI), locomotor ability, and mRNA and miRNA expressions in the hippocampus and blood were observed. To investigate potential sex differences in the effects of prenatal gamma irradiation, we conducted a parallel study on female B6C3F1 mice. The results showed significant reductions in the weight of the lungs and left kidney in prenatally irradiated female offspring, accompanied by significantly increased fat deposits in the mesentery, retroperitoneal, and left perigonadal areas. Despite these systemic changes, no cellular alterations were observed in the subgranular zone (immature neurons) or the hilus of the dentate gyrus (mature neurons and glial cells, including astrocytes, microglia, and oligodendrocyte progenitor cells). However, significant increases in hippocampal mRNA expression were detected for genes such as H2bc24, Fos, Cd74, Tent5a, Traip, and Sap25. Conversely, downregulation of mRNAs Inpp5j and Gdf3 was observed in whole blood. A Venn diagram highlighted the differential expression of two mRNAs, Ttn and Slc43a3, between the hippocampus and whole blood. Comparisons between prenatally irradiated male and female B6C3F1 mice revealed sex-specific differences. In whole blood, 4 mRNAs (Scd1, Cd59b, Vmn1r58, and Gm42427) and 1 miRNA (mmu-miR-8112) exhibited differential expression. In the hippocampus, 12 mRNAs and 2 novel miRNAs were differentially expressed between the sexes. qRT-PCR analysis validated the upregulation of H2bc24, Fos, Cd74, and Tent5a in the female hippocampus. These gene expression changes may be associated with the increased fat deposition observed following chronic low-dose-rate gamma irradiation exposure. This study underscores the importance of investigating sex-specific biological responses to prenatal gamma irradiation and highlights potential molecular pathways linked to observed physiological changes. Full article