Search Results (899)

ALS is a severe neuromuscular disease classically characterized by the progressive loss of motor neurons, leading to incremental muscle weakness and eventually death. Current treatment options for ALS have proven to have limited effect, merely delaying the progression of symptoms and prolonging patient survival. This motor neuron subtype-related differential vulnerability has been linked to neuron excitability, metabolism, and protein aggregation. Calcium dysregulation, which serves as an important second messenger in neural signaling pathways, has been implicated in each of these mechanisms and represents a potential target for therapeutic intervention. Armed with cutting-edge tools for visualizing and recording calcium transients in vivo, ALS researchers have delved deeper into the role of calcium dysregulation in disease in recent years. Vulnerable motor neuron populations display an excess of calcium-permeable ion channels together with reduced expression of calcium-binding proteins, generating a cellular environment primed for excitotoxic stress. Loss of inhibitory synaptic input further heightens susceptibility to calcium overload. Paradoxically, some evidence suggests that elevated neuronal activity can exert neuroprotective effects, highlighting the complexity of activity-dependent calcium signaling in ALS. Additionally, ALS-related toxic protein accumulation disrupts calcium homeostasis, contributing to endoplasmic reticulum stress and mitochondrial dysfunction. Emerging data indicate that calcium dysregulation impairs neuron-glia communication, amplifying neuroinflammation and accelerating disease progression. This review aims to synthesize current evidence on how calcium imbalance contributes to motor neuron vulnerability and degeneration in ALS. By exploring the cellular, synaptic, and network-level mechanisms of calcium dysregulation in ALS, the review examines its interplay with mitochondrial and ER stress and explores its impact on neuron-glia interactions with the aim of synthesizing key mechanistic insights into the disease pathogenesis and therapeutic targets. Full article

The heart’s performance relies on its contractile and rhythmic properties, which are modulated not only by extrinsic autonomic inputs but also by the intrinsic cardiac nervous system (ICNS), a distributed network of intracardiac ganglia and neurons that integrates local sensory, autonomic, and inflammatory signals. Growing evidence indicates that cardiac fibrosis and neuronal remodeling are intertwined processes within this network. This review synthesizes current knowledge on molecular, structural, and functional remodeling of the ICNS to drive neurofibrosis, autonomic imbalance, and arrhythmogenesis. We outline ICNS anatomy and neurochemical diversity, then summarize core fibrotic mechanisms, fibroblast activation, extracellular matrix dynamics, and inflammatory signaling, and map these onto intracardiac ganglia. Across diabetes, myocardial infarction, heart failure, and neuroinflammatory states, shared pathways (e.g., IL-6/STAT3, TGF-β/SMAD, PI3K/AKT, MAPK/ERK, oxidative stress) suppress neuronal excitability, promote neuron–glia–fibroblast coupling, and culminate in neurofibrotic remodeling. We integrate functional data linking these changes to autonomic dysregulation and arrhythmia vulnerability. Future priorities involve constructing detailed human ICNS atlases and applying single-cell and spatial multi-omics to better characterize intracardiac neurons, their circuitry, and their interactions with fibroblasts and immune cells. These insights will be essential to inform targeted neuromodulation and anti-fibrotic interventions. The ICNS is a dynamic regulatory hub whose cells and circuits participate directly in cardiac fibrosis and electrical instability. Recognizing neurofibrosis as a companion process to myocardial fibrosis reframes therapeutic strategy toward preserving both neural and myocardial integrity. Full article

Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by mutations in the MeCP2 gene, predominantly affecting females. Recent work with MeCP2-deficient mouse models showed a significant role in glutamatergic transmission, specifically microglia-produced glutamate and glutaminase upregulation, in RTT pathology. The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) is a potent glutaminase inhibitor; however, its use is limited due to systemic toxicities arising from its non-specific inhibition of glutamine-utilizing reactions. In this work, we determined whether dendrimer conjugation of a DON analog, TTM020 (or D-TTM020), results in targeted microglial glutaminase inhibition and behavioral changes in Mecp2 KO and heterozygous mice upon systemic administration. D-TTM020 at 1 mg/kg (drug basis) selectively and significantly inhibits glutaminase enzyme activity in the microglia of Mecp2 KO mice. Biweekly systemic treatment with 1 mg/kg of D-TTM020 improved the neurobehavioral phenotype in symptomatic Mecp2 KO and het mice. D-TTM020 also restored long-term retrieval of conditioned fear memory and improved cue responses during fear extinction after 8 weeks of treatment in symptomatic Mecp2 het mice. Our data indicate that selectively targeting glutamine metabolism in dysregulated glia using dendrimers represents a promising strategy that may offer a therapeutic approach for addressing glutamate dysregulation in RTT. Full article

Current research on glial cells has primarily focused on central nervous system glial cells (CNS glia), with relatively fewer studies on EGCs. Given the critical role of EGCs in maintaining intestinal homeostasis and neural function, this study aimed to investigate their immunomodulatory effects under inflammatory conditions. Primary EGCs were isolated and an inflammatory model was established by treatment with lipopolysaccharide (LPS). Following LPS induction, cellular samples were collected for transcriptomic analysis to identify differentially expressed genes. The analysis revealed that 88 genes were significantly altered, with 60 upregulated and 28 downregulated. Through Gene Ontology (GO) classification, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway mapping, and protein–protein interaction (PPI) network analysis, several key regulatory genes were identified: chemokine-related genes (IL8L2, IL8L1, CCL4, CCL5, and CX3CL1); negative feedback regulation-related genes (TNFAIP3 and ZC3H12A); homeostasis-maintaining genes (C1QB and LY86); and arachidonic acid metabolism-related genes (PTGS2 and GGT2). Under LPS stimulation without impairing EGC viability, EGCs may recruit immune cells by regulating the aforementioned genes. Additionally, arachidonic acid and its metabolites likely play important regulatory roles in EGC-mediated immunomodulation. These findings provide new theoretical insights and potential targets for further elucidating the pathogenesis of intestinal inflammation and developing targeted therapies. Full article

Background/Objectives: White matter degeneration is a significant and early mediator of cognitive impairment in Alzheimer’s disease (AD), yet the critical pathologic features remain poorly understood, under-detected, and therapeutically untargeted. Herein, we characterize molecular features of white matter glial cells in AD brains and assess the utility of non-invasive approaches for detecting related abnormalities in extracellular vesicles (EVs) isolated from serum (SEV). In addition, results from unfractionated (SEV-T) and O4 sulfatide-selected SEVs were compared to determine whether white matter abnormalities were detected with greater sensitivity in oligodendrocyte-specific SEVs (SEV-O4). Methods: Oligodendrocyte glycoprotein and astrocyte mRNA levels were measured in postmortem human AD and control frontal lobe white matter by RT-PCR. Immunoreactivity to oligodendrocyte glycoproteins, astrocyte structural proteins, neurofilament light chain (NfL), and aspartyl-asparaginyl-β-hydroxylase (ASPH) was measured by ELISA in SEV-T and SEV-O4 from patients with moderate AD or normal aging. Results: AD brain pathology was associated with significantly reduced mRNA expression of multiple oligodendrocyte glycoproteins and increased mRNA expression of astrocytic structural genes. SEV analyses demonstrated significantly increased immunoreactivity to 2′,3′-cyclic nucleotide 3′ phosphodiesterase (CNPase), myelin-associated glycoprotein 1 (MAG1), astrocyte proteins, and ASPH, a potent activator of Notch and myelin-regulated homeostatic functions. There were no significant benefits of measuring SEV-O4 compared with SEV-T immunoreactivity. Conclusions: AD is associated with significant molecular abnormalities in oligodendrocyte and astrocyte function in brain tissue. The abnormalities detected in SEVs likely reflect oligodendrocyte injury and degeneration, as well as astrocytic activation. The findings suggest that low-invasive SEV approaches, including the novel analysis of ASPH upregulation, can be used to detect and monitor AD white matter degeneration. Full article

Spinal cord injury (SCI) remains a major clinical challenge due to the limited regenerative capacity of the central nervous system (CNS). Effective scaffolds for repair must combine mechanical compatibility with host tissue, controlled degradation matching the time course of regeneration, and microarchitectural features that promote neuronal survival. Electrospun nanofibrous scaffolds mimic the structural and mechanical features of the extracellular matrix, providing critical cues for neuronal adhesion and glial modulation in neural regeneration. Here, we fabricated biodegradable poly(lactic acid)/poly(ε-caprolactone) (PLA/PCL) scaffolds using a dichloromethane/tetrahydrofuran (DCM/THF) solvent system to induce surface porosity via solvent-driven phase separation. The DCM/THF solvent system formulation produced nanofibers with porous surfaces and increased area for cell interaction. PLA/PCL scaffolds showed a Young’s modulus of ~26 MPa and sustained degradation, particularly under oxidative conditions simulating the post-injury microenvironment. In vitro, these scaffolds enhanced neuronal density up to fivefold and maintained ~80% viability over 10 days in primary neuron–glia cultures. Morphometric analysis revealed that DCM/THF-based scaffolds supported astrocytes with preserved process complexity and reduced circularity, indicative of a less reactive morphology. In contrast, scaffolds fabricated with 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) displayed reduced bioactivity and promoted morphological features associated with astrocyte reactivity, including cell rounding and process retraction. These findings demonstrate that solvent-driven control of scaffold microarchitecture is a powerful strategy to enhance neuronal integration and modulate glial morphology, positioning DCM/THF-processed PLA/PCL scaffolds as a promising platform for CNS tissue engineering. Full article

Spinal cord injury (SCI) remains one of the most formidable challenges in regenerative medicine, often resulting in permanent loss of motor, sensory, and autonomic function. Cell-based therapies offer a promising path toward repair by providing donor neurons and glia capable of integrating into host circuits, modulating the injury environment, and restoring function. Early studies employing fetal neural tissue and neural progenitor cells (NPCs) have demonstrated proof-of-principle for survival, differentiation, and synaptic integration. More recently, pluripotent stem cell (PSC)-derived donor populations and engineered constructs have expanded the therapeutic repertoire, enabling precise specification of interneuron subtypes, astrocytes, and oligodendrocytes tailored to the injured spinal cord. Advances in genetic engineering, including CRISPR-based editing, trophic factor overexpression, and immune-evasive modifications, are giving rise to next-generation donor cells with enhanced survival and controllable integration. At the same time, biomaterials, pharmacological agents, activity-based therapies, and neuromodulation strategies are being combined with transplantation to overcome barriers and promote long-term recovery. In this review, we summarize progress in designing and engineering donor cells and tissues for SCI repair, highlight how combination strategies are reshaping the therapeutic landscape, and outline opportunities for next-generation approaches. Together, these advances point toward a future in which tailored, multimodal cell-based therapies achieve consistent and durable restoration of spinal cord function. Full article

Background/Objective: Parkinson’s disease (PD) has long been viewed from a neurocentric perspective; however, increasing evidence indicates that glial dysfunction also contributes to dopaminergic neurodegeneration. Although neurotoxic glial phenotypes have been described in amyotrophic lateral sclerosis and Alzheimer’s disease in vivo models, it remains unclear whether similar states arise in the pathological milieu of PD. This study aimed to determine whether glial cells with intrinsic neurotoxic properties emerge in the substantia nigra pars compacta (SNpc) in a PD context. Methods: The classical 6-hydroxydopamine rat model was used to obtain glial cultures from the ipsilateral, toxin-damaged SNpc. These cultures were characterized by quantifying cell number and morphology, as well as by assessing the expression of glial markers. Their neurotoxic potential was evaluated in vitro through co-cultures with PC12 cells, and in vivo by transplanting the isolated cells into the SNpc of naïve rats. Assessments included PC12 cell survival, and integrity of the nigrostriatal pathway and motor performance in the cylinder test. Results: Ipsilateral SNpc cultures yielded 25-fold more cells than contralateral controls. Cultured cells co-expressed astrocytic and microglial markers, thus defining a population of damage-derived reactive glia (DDRG). When co-cultured, DDRG reduced PC12 cell survival, whereas control glial cells showed no neurotoxic effects. In vivo, DDRG transplantation induced a dose-dependent loss of dopaminergic neurons and motor impairments, while vehicle and control glia produced no detectable effects. Conclusions: Our findings suggest that glial cells emerging from a neuroinflammatory/neurodegenerative environment in the SNpc may contribute to dopaminergic neuron loss. Within the context of the experimental PD model used, DDRG appears to represent a glial population with potential pathogenic relevance and may constitute a candidate target for further investigation as a therapeutic strategy in Parkinson’s disease. Full article

Background: Honeybees sustain vital ecological roles through foraging behavior, which provides pollination services and is likely regulated by dopamine signaling coupled to brain energy metabolism. However, the genetic and metabolic mechanisms underlying this regulation remain unclear. Methods: We treated honeybee workers with the dopamine receptor agonist bromocriptine and employed an integrative approach, combining liquid chromatography–mass spectrometry (LC–MS) metabolomics with single-nucleus RNA sequencing (snRNA-seq). Results: Metabolomics revealed increased levels of N6-carboxymethyllysine (CML) and a coordinated shift in central carbon metabolites, including higher glucose, pyruvate, and lactate within glycolysis, and ribose-5-phosphate in the pentose phosphate pathway (PPP). Integration with transcriptomics showed heterogeneous responses: glial cells exhibited higher glycolysis pathway scores and upregulated hexokinase expression compared to neurons, whereas major PPP enzymes were upregulated in both glial and neuronal subsets. Conclusions: These findings suggest that dopamine receptor activation is associated with altered whole-brain metabolic profiles and concurrent, cell-type-specific upregulation of glycolytic and PPP enzyme genes, particularly in glia. This study characterizes these neuro-metabolic associations, offering insights into the cellular and metabolic basis of foraging behavior in worker bees. Full article

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs (2002–2012) estimated ~99.6% attrition, while PD programs (1999–2019) achieved an overall success rate of ~14.9%. In vitro platforms are assessed, ranging from immortalized neuronal lines and primary cultures to human-induced pluripotent stem cell (iPSC)-derived neurons/glia, neuron–glia co-cultures (including neuroinflammation paradigms), 3D spheroids, organoids, and blood–brain barrier (BBB)-on-chip systems. Complementary in vivo toxin, pharmacological, and genetic models are discussed for systems-level validation and central nervous system (CNS) exposure realism. The therapeutic synthesis focuses on AD, covering symptomatic drugs, anti-amyloid immunotherapies, tau-directed approaches, and repurposed drug classes that target metabolism, neuroinflammation, and network dysfunction. This review links experimental models to translational decision-making, focusing primarily on AD and providing a brief comparative context from other NDDs. It also covers emerging targeted protein degradation (PROTACs). Key priorities include neuroimmune/neurovascular human models, biomarker-anchored adaptive trials, mechanism-guided combination DMTs, and CNS PK/PD-driven development for brain-directed degraders. Full article

Traumatic brain injury (TBI) often leads to long-lasting motor deficits, but the underlying cellular mechanisms still remain poorly understood. In this study, we examined glial and neuronal responses after focal cortical aspiration injury of the right hindlimb sensorimotor cortex in adult male rats. This is a model we have previously shown induces persistent gait asymmetry and postural deficits. Immunohistochemical analysis of activated microglia/macrophages (CD11b, IBA-1), astrocytes (GFAP), and neurons (NeuN) was performed bilaterally in the peri-lesional cortex at 3, 7, 14, 21, and 28 days post-injury (n = 3–6 per time point). The injury induced an early, sharply localized increase in CD11b-positive myeloid cells in the injured hemisphere, suggesting an activation of both resident microglia and infiltrating monocyte-derived cell. This was followed by a more sustained IBA-1-positive microglial activation that gradually extended contralaterally. Astrocytic activation showed a delayed but prolonged profile, rising ipsilaterally within the first week, peaking around two weeks, and becoming bilaterally elevated by four weeks. Sham-operated animals showed only basal glial immunoreactivity without signs of hypertrophy or reactive morphology at any time point. NeuN immunoreactivity remained stable across timepoints, suggesting preservation of neuronal soma labeling without evidence of overt secondary neuronal loss. These findings reveal a staged and spatially distinct glial response to focal cortical injury, with early myeloid activation, prolonged microglial reactivity, and delayed bilateral astrogliosis. Together, these findings are consistent with the possibility that persistent motor deficits after focal TBI arise from both primary tissue loss within the lesion core and peri-lesional glial remodeling, highlighting glial–neuronal interactions as a potential therapeutic target. Full article

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease characterized by cerebellar ataxia and retinal degeneration, caused by an abnormal expansion of CAG repeats at the ATXN7 gene. Disease onset and progression vary among patients, underscoring the need for novel tools to improve disease monitoring. Circulating miRNAs represent a promising prognostic tool, due to their minimally invasive sampling and high stability. The aim of this study was to assess the expression of twelve circulating miRNAs associated with neurodegeneration in plasma samples from SCA7 patients and in an inducible SCA7 glial cell model. A comparison of SCA7 patients and controls revealed that nine miRNAs exhibited significantly higher expression. Furthermore, comparison of patients with different SCA7 phenotypes to controls revealed that most miRNAs were overexpressed in plasma from early-onset patients corresponding to the clinically more severe phenotype. Regarding the cell model, we identified three miRNAs that were dysregulated; however, only hsa-miR-342-5p displayed a pattern consistent with that observed in the plasma of patient. Our findings indicate that hsa-miR-342-5p is differentially expressed in the plasma of patients and the SCA7 cellular model, implying that it can serve as a biomarker and facilitate the identification of novel processes involved in SCA7. Full article

The enteric nervous system (ENS) constitutes a highly organized and intricate neuronal network comprising two principal plexuses: myenteric and submucosal. These plexuses consist of neurons and enteric glial cells (EGCs). Neurons ensure innervation throughout the intestinal wall, whereas EGCs, distributed within the mucosa, contribute to epithelial barrier integrity and modulation of local inflammatory responses. The ENS orchestrates essential gastrointestinal functions, including motility, secretion, absorption, vascular regulation, and immune interactions with gut microbiota. Under physiological conditions, intestinal homeostasis involves moderate generation of reactive oxygen species (ROS) through endogenous processes such as mitochondrial oxidative phosphorylation. Cellular antioxidant systems maintain redox equilibrium; however, excessive ROS production induces oxidative stress, promoting EGCs activation toward a reactive phenotype characterized by pro-inflammatory cytokine release. This disrupts neuron–glia communication, predisposing to enteric neuroinflammation and neurodegeneration. Obesity, associated with hyperglycemia, hyperlipidemia, and micronutrient deficiencies, enhances ROS generation and inflammatory cascades, thereby impairing ENS integrity. Nevertheless, non-pharmacological strategies—including synthetic and natural antioxidants, bioactive dietary compounds, probiotics, and prebiotics—attenuate oxidative and inflammatory damage. This review summarizes preclinical and clinical evidence elucidating the interplay among the ENS, obesity-induced oxidative stress, inflammation, and the modulatory effects of antioxidant interventions. Full article

Spinal cord injury (SCI) is a debilitating condition resulting in a range of neurological impairments up to complete loss of function below the level of injury. With current clinical management limited to decompression and stabilisation of the injury, there is urgent need to develop effective restorative treatments. In animal models, cell transplantation therapies are being tested that utilise different cell types including olfactory ensheathing cells (OECs), a type of glial cell, to support and promote regeneration. While OECs have a unique combination of properties highly suitable for SCI repair, their efficacy and consistency need to be improved. Evidence suggests a combinational approach using growth factors or compounds alongside OECs may stimulate their innate properties and alter the internal milieu of an injury site in favour of neural repair. Naturally, there is intricate interplay between various growth factors and OECs during development of the olfactory system, and in injury and repair events, which regulate their migration, phagocytosis, and proliferation. Therefore, exploiting different growth factors to selectively enhance OECs’ therapeutic potential could lead to restorative treatment of SCI. While some studies have already explored using growth factors to treat SCI in animal models, an optimal ‘cocktail’ has yet to be identified. In seeking to identify such a cocktail, this review presents the current understanding of SCI and the therapeutic potential of OECs and explores combined use of growth factors and OECs to improve treatment outcomes. Full article

Mild traumatic brain injury (mTBI) disrupts hippocampal network function through coordinated alterations in glial reactivity, synaptic integrity, and adult neurogenesis. Effective therapeutic approaches targeting these interconnected processes remain limited. Lipid-derived molecules capable of modulating these mTBI-induced disturbances are emerging as promising neuroprotective candidates. Here, we investigated the effects of N-stearidonylethanolamine (SDEA), an ω-3 ethanolamide, in a mouse model of mTBI. SDEA treatment attenuated astrocytic reactivity, restored Arc expression, and improved dendritic spine density and morphology in the CA1 hippocampal area. In the dentate gyrus, mTBI reduced Ki-67-indexed proliferation while leaving DCX-positive immature neurons unchanged, and SDEA partially rescued proliferative activity. These effects were accompanied by improvements in anxiety-like behavior and working-memory performance. Together, these findings demonstrate that SDEA modulates several key components of the glia-synapse-neurogenesis axis and supports functional recovery of hippocampal circuits following mTBI. These results suggest that ω-3 ethanolamides may represent promising candidates for multi-target therapeutic strategies in mTBI. Full article