Hepatic encephalopathy, defined as neuropsychiatric dysfunction secondary to liver disease, is a frequent decompensating event in cirrhosis. Its clinical impact is highlighted by a notable increase in patient mortality rates and a concomitant reduction in overall quality of life. Systemically, liver disease, liver function failure, portosystemic shunting, and associated multi-organ dysfunction result in the increase of disease-causing neurotoxins in the circulation, which impairs cerebral homeostasis. Key circulating neurotoxins are ammonia and inflammatory mediators. In the brain, pathophysiology is less well understood, but is thought to be driven by glial cell dysfunction. Astrocytes are the only brain resident cells that have ammonia-metabolizing machinery and are therefore putatively most susceptible to ammonia elevation. Based on a large body of mostly in vitro evidence, ammonia-induced cellular and molecular disturbances include astrocyte swelling and oxidative stress. Microglia, the brain resident macrophages, have been linked to the translation of systemic inflammation to the brain microenvironment. Recent evidence from animal studies has provided novel insights into old and new downstream effects of astrocyte and microglial dysfunction such as toxin clearance disruption and myeloid cell attraction to the central nervous system parenchyma. Furthermore, state of the art research increasingly implicates neuronal dysfunction and possibly even irreversible neuronal cell death. Cell-type specific investigation in animal models highlights the need for critical revision of the contribution of astrocytes and microglia to well-established and novel cellular and molecular alterations in hepatic encephalopathy. In this review, we therefore give a current and comprehensive overview of causes, features, and consequences of astrocyte and microglial dysfunction in hepatic encephalopathy, including areas of interest for future investigation.

JOURNAL/nrgr/04.03/01300535-202507000-00027/figure1/v/2024-09-09T124005Z/r/image-tiff An imbalance in adenosine-mediated signaling, particularly the increased A2AR-mediated signaling, plays a role in the pathogenesis of Parkinson's disease. Existing therapeutic approaches fail to alter disease progression, demonstrating the need for novel approaches in PD. Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease. However, the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown. The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling. Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test. Immunoblot, quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen. Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals. A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen. Treatment with intermittent theta burst stimulation began 7 days after the lesion, coinciding with the onset of motor symptoms. After treatment with prolonged intermittent theta burst stimulation, complete motor recovery was observed. This improvement was accompanied by downregulation of the eN/CD73-A2AR pathway and a return to physiological levels of A1R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation. Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A1R and elevated the expression of A2AR. Intermittent theta burst stimulation reversed these effects by restoring the abundances of A1R and A2AR to control levels. The shift in ARs expression likely restored the balance between dopamine-adenosine signaling, ultimately leading to the recovery of motor control.

Supervised and unsupervised methods have emerged to address the complexity of single cell data analysis in the context of large pools of independent studies. Here, we present ClusterFoldSimilarity (CFS), a novel statistical method design to quantify the similarity between cell groups across any number of independent datasets, without the need for data correction or integration. By bypassing these processes, CFS avoids the introduction of artifacts and loss of information, offering a simple, efficient, and scalable solution. This method match groups of cells that exhibit conserved phenotypes across datasets, including different tissues and species, and in a multimodal scenario, including single-cell RNA-Seq, ATAC-Seq, single-cell proteomics, or, more broadly, data exhibiting differential abundance effects among groups of cells. Additionally, CFS performs feature selection, obtaining cross-dataset markers of the similar phenotypes observed, providing an inherent interpretability of relationships between cell populations. To showcase the effectiveness of our methodology, we generated single-nuclei RNA-Seq data from the motor cortex and spinal cord of adult mice. By using CFS, we identified three distinct sub-populations of astrocytes conserved on both tissues. CFS includes various visualization methods for the interpretation of the similarity scores and similar cell populations.

Non-neuronal cells constitute a significant portion of brain tissue and are seen as having key roles in brain homeostasis and responses to challenges. This review illustrates how non-neuronal biology can bring new perspectives to animal welfare through understanding mechanisms that determine welfare outcomes and highlighting interventions to improve welfare. Most obvious in this respect is the largely unrecognised relevance of neuroinflammation to animal welfare which is increasingly found to have roles in determining how animals respond to challenges. We start by introducing non-neuronal cells and review their involvement in affective states and cognition often seen as core psychological elements of animal welfare. We find that the evidence for a causal involvement of glia in cognition is currently more advanced than the corresponding evidence for affective states. We propose that translational research on affective disorders could usefully apply welfare science derived approaches for assessing affective states. Using evidence from translational research, we illustrate the involvement of non-neuronal cells and neuroinflammatory processes as mechanisms modulating resilience to welfare challenges including disease, pain, and social stress. We review research on impoverished environments and environmental enrichment which suggests that environmental conditions which improve animal welfare also improve resilience to challenges through balancing pro- and anti-inflammatory non-neuronal processes. We speculate that non-neuronal biology has relevance to animal welfare beyond neuro-inflammation including facilitating positive affective states. We acknowledge the relevance of neuronal biology to animal welfare whilst proposing that non-neuronal biology provides additional and relevant insights to improve animals' lives.

Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasome-dependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.

The prefrontal cortex (PFC) is an essential driver of cognitive, affective, and motivational behavior. There is clear evidence that the neuroimmune system directly influences PFC synapses, in addition to its role as the first line of defense against toxins and pathogens. In this review, we first describe the core structures that form the tetrapartite PFC synapse, focusing on the signaling microdomain created by astrocytic cradling of the synapse as well as the emerging role of the extracellular matrix in synaptic organization and plasticity. Neuroimmune signals (e.g. pro-inflammatory interleukin 1β) can impact the function of each core structure within the tetrapartite synapse, as well as promote intra-synaptic crosstalk, and we will provide an overview of recent advances in this field. Finally, evidence from post mortem human brain tissue and preclinical studies indicate that inflammation may be a key contributor to PFC dysfunction. Therefore, we conclude with a mechanistic discussion of neuroimmune-mediated maladaptive plasticity in neuropsychiatric disorders, with a focus on alcohol use disorder (AUD). Growing recognition of the neuroimmune system's role as a critical regulator of the PFC tetrapartite synapse provides strong support for targeting the neuroimmune system to develop new pharmacotherapeutics.

Lead, a toxic heavy metal, is prevalent in various industrial applications, contributing to environmental contamination and significant health concerns. Lead affects various body systems, especially the brain, causing long-lasting cognitive and behavioral changes. While most studies have focused on continuous lead exposure, intermittent exposure, such as that caused by migration or relocations, has received less attention. Importantly, lead exposure intensifies the severity of Parkinson's disease (PD) and dementia with Lewy bodies, diseases involving the accumulation of alpha-synuclein (aSyn) in the brain and in the gut. Although the precise mechanisms underlying these observations remain unclear, oxidative stress and mitochondrial dysfunction likely play a role. Here, we investigated how two different profiles of lead exposure - continuous and intermittent - affect models of synucleinopathies. We found that lead exposure enhances the formation of aSyn inclusions, resulting in an increase in both their number and size in cell models. In addition, we found that animals injected with aSyn pre-formed fibrils display serine 129-phosphorylated aSyn inclusions and a reduction in astrocytes in the substantia nigra. These animals also display neuronal damage and alterations in locomotor activity, exploration behavior, anxiety, memory impairments and hypertension. Our results suggest a mechanistic link between environmental lead exposure and the onset and progression of diseases associated with aSyn pathology. Understanding the molecular and cellular interactions between lead and aSyn is crucial for shaping public health policies and may provide novel insight into strategies for mitigating the impact of environmental toxins on neurodegenerative processes involved in Parkinson's disease and related synucleinopathies.

Microglia and astrocytes are central to the pathogenesis and progression of Alzheimer's Disease (AD), working both independently and collaboratively to regulate key pathological processes such as β-amyloid protein (Aβ) deposition, tau aggregation, neuroinflammation, and synapse loss. These glial cells interact through complex molecular pathways, including IL-3/IL-3Ra and C3/C3aR, which influence disease progression and cognitive decline. Emerging research suggests that modulating these pathways could offer therapeutic benefits. For instance, recombinant IL-3 administration in mice reduced Aβ plaques and improved cognitive functions, while C3aR inhibition alleviated Aβ and tau pathologies, restored synaptic function, and corrected immune dysregulation. However, the effects of these interactions are context-dependent. Acute C3/C3aR activation enhances microglial Aβ clearance, whereas chronic activation impairs it, highlighting the dual roles of glial signaling in AD. Furthermore, C3/C3aR signaling not only impacts Aβ clearance but also modulates tau pathology and synaptic integrity. Given AD's multifactorial nature, understanding the specific pathological environment is crucial when investigating glial cell contributions. The interplay between microglia and astrocytes can be both neuroprotective and neurotoxic, depending on the disease stage and brain region. This complexity underscores the need for targeted therapies that modulate glial cell activity in a context-specific manner. By elucidating the molecular mechanisms underlying microglia-astrocyte interactions, this research advances our understanding of AD and paves the way for novel therapeutic strategies aimed at mitigating neurodegeneration and cognitive decline in AD and related disorders.

The blood-brain barrier (BBB) is a semi-permeable membrane in physiological conditions, but in pathologies like multiple sclerosis (MS) and ischemic stroke (IS), its permeability increases. In this review, we focus on neutrophils and their interaction with cellular components of the BBB: endothelial cells (EC), pericytes (PC), and astrocytes (AC). Nowadays, neutrophils receive more attention, mostly due to advanced research techniques that show the complexity of their population. Additionally, neutrophils have the ability to secrete extracellular vesicles (EVs), reactive oxygen species (ROS) and cytokines, which both destroy and restore the BBB. Astrocytes, PCs, and ECs also have dual roles in the pathogenesis of MS and IS. The interaction between neutrophils and cellular components of the BBB provides us with a wider insight into the pathogenesis of common diseases in the central nervous system. Further, we comprehensively review knowledge about the influence of neutrophils on the BBB in the context of MS and IS. Moreover, we describe new therapeutic strategies for patients with MS and IS like cell-based therapies and therapies that use the neutrophil function.

Astrocytes play pivotal roles in central nervous system (CNS) homeostasis, with emerging evidence implicating astrocyte-derived lactoferrin (Lf) in neurodevelopmental and neurodegenerative processes. This study investigates Lf's functional significance in spinal cord integrity using astrocyte-specific Lf knockout (cKO) mice. Behavioral analyses of 1-month-old male cKO mice revealed impaired motor coordination (increased balance beam scores and prolonged pole-climbing latency) and delayed nociceptive responses (increased thermal withdrawal latency). Morphological assessments demonstrated neuron-specific pathology: motor neurons exhibited atrophy and reduced Nissl substance staining, spinal ganglion cells showed quantitative depletion with vacuolar degeneration, and protein expression analyses confirmed declines in neuronal markers (NeuN), synaptic components (SNAP25, PSD95), axonal and myelin related proteins (NF-L, MBP), and neurotransmitter transporters (AChE). Notably, glial cell populations remained unaffected. Mechanistic investigations identified reduced spinal cholesterol content accompanied by downregulation of cholesterol biosynthesis and transport regulators (Srebp2, HMGCR, ApoE, ABCA1) and activation of AMP-activated protein kinase (AMPK). These findings establish astrocytic Lf as a critical modulator of cholesterol metabolism essential for maintaining neuronal structural and functional integrity in the spinal cord. The discovered Lf-cholesterol regulatory axis provides novel insights into the pathogenesis of spinal cord disorders and highlights potential therapeutic targets for neurodegenerative conditions.

Viruses pose a significant challenge and threat to human health, as demonstrated by the current COVID-19 pandemic. Neurodegeneration, particularly in the case of Alzheimer's disease (AD), is significantly influenced by viral infections. AD is a neurodegenerative disease that affects people of all ages and poses a significant threat to millions of individuals worldwide. The precise mechanism behind its development is not yet fully understood; however, the emergence and advancement of AD can be hastened by various environmental factors, such as bacterial and viral infections. There has been a longstanding suspicion that the herpes simplex virus-1 (HSV-1) may have a role to play in the development or advancement of AD. Reactivation of HSV-1 could potentially lead to damage to neurons, either by direct means or indirectly by triggering inflammation. This article provides an overview of the connection between HSV-1 infections and immune cells (astrocytes, microglia, and oligodendrocytes) in the progression of AD. It summarizes recent scientific research on how HSV-1 affects neurons, which could potentially shed light on the clinical features and treatment options for AD. In addition, the paper has explored the impact of HSV-1 on neurons and its role in various aspects of AD, such as Aβ secretion, tau hyperphosphorylation, metabolic dysregulation, oxidative damage, apoptosis, and autophagy. It is believed that the immune response triggered by HSV-1 reactivation plays a role in the development of neurodegeneration in AD. Despite the lack of a cure for AD, researchers have made significant efforts to study the clinical and pathological aspects of the disease, identify biomarkers, and gain insight into its underlying causes. The goal is to achieve early diagnosis and develop treatments that can modify the progression of the disease. The current article discusses the most promising therapy for combating the viral impacts, which provides additional evidence for the frequent reactivations of latent HSV-1 in the AD brain. However, further research is still required to establish the molecular and cellular mechanisms underlying the development of AD through the reactivation of HSV-1. This could potentially lead to new insights in drug development aimed at preventing HSV-1 reactivation and the subsequent development and progression of AD.

Glial cells play pivotal roles in homeostatic regulation and driving reactive pathologic changes after nerve injury. Connexins (Cxs) and pannexins (Panxs) have emerged as seminal proteins implicated in cell-cell communication, exerting a profound impact on the response processes of glial cell activation, proliferation, protein synthesis and secretion, as well as apoptosis following nerve injury. These influences are mediated through various forms, including protein monomers, hemichannel (HC), and gap junction (GJ), mainly by regulating intercellular or intracellular signaling pathways. Multiple Cx and Panx isoforms have been detected in central nervous system (CNS) or peripheral nervous system (PNS). Each isoform exhibits distinct cellular and subcellular localization, and the differential regulation and functional roles of various protein isoforms are observed post-injury. The quantitative and functional alterations of the same protein isoform in different studies remain inconsistent, attributable to factors such as the predominant mode of protein polymerization, the specific injury model, and the injury site. Similarly, the same protein isoforms have different roles in regulating the response processes after nerve injury, thus exerting a double-edged sword effect. This review describes the regulatory mechanisms and bidirectional effects of Cxs and Panxs. Additionally, it surveys the current status of research and application of drugs as therapeutic targets for neuropathic injuries. We summarize comprehensive and up-to-date information on these proteins in the glial cell response to nerve injury, providing new perspectives for future mechanistic exploration and development of targeted therapeutic approaches.

Coxsackievirus A16 (CVA16), a major pathogen responsible for hand-foot-and-mouth disease (HFMD) in children, has frequently replaced Enterovirus A71 as the predominant causative agent in China and other Asia-Pacific regions. The lack effective drugs and vaccines against this virus exacerbates the concerns on its outbreaks. Clinical reports and laboratory studies indicate that CVA16 infection may lead to neurological injury, but the precise mechanisms remain elusive. In this study, we meticulously established a CVA16 murine disease model using 3-week-old hSCARB2 knock-in mice through intracranial inoculation. Within 4-7 days post-infection, the infected mice exhibited severe neurological symptoms featured as limb paralysis, hind limb weakness and ataxia. Furthermore, high viral loads were detected in the brain, spleen, skeletal muscle tissues, indicating a systemic infection. A robust cytokine response was observed, characterized with the elevation of TNF-α, IL-12 (p40), IL-10 and MIP-1β. Histological and immunofluorescence staining revealed extensive inflammation, marked by the concentrated infiltration of astrocytes cells, as well as severe neurological injury, which included hypertrophic and extended pseudopodia microglia, increased astrocytes with long and stretched protuberances, markedly decreased neuronal cell bodies and nerve fibers in brain. No visible pathological changes were observed in spinal cord tissues. RNA sequencing and immunofluorescence staining of brain tissue verification assays indicated that the neurological injury may engage in TLR2/MYD88/TNF-α/CXCL1 signal pathway. Over all, this work addressed the gap in the availability of CVA16 disease rodent model for vaccine development and provided novel insights into the mechanisms underlying neurological injury caused by enteroviruses and other neurotropic viruses.

Hepatic encephalopathy (HE) is a neuropsychiatric complication of liver failure. Previous studies described astroglia alterations in HE, but regional changes have not been well investigated. This study addresses regional astroglial response by exploring glial fibrillary acidic protein (GFAP) immunoreactivity in cortical structures including somatosensory (S1Tr and S1BF), piriform (Pir), and perirhinal (PRh) cortices, and subcortical regions including corpus callosum (CC), ventromedial thalamus (VMT), mammillothalamic tract (MTT), and dorsomedial hypothalamic nucleus (DHN) in rats with acute liver failure (ALF) sacrificed at coma stage. Our data showed decreased numbers of astrocytes in S1Tr, Pir, and CC in ALF rats. GFAP-immunoreactive cells were increased within other regions including PRh, VMT, MTT, and DHN. Cell morphometric analysis showed significant increase in GFAP-immunoreactive astrocyte processes and cell bodies in cortical and subcortical regions but not in CC and DHN. However, astrocyte perimeters were increased, particularly in S1Tr and VMT. Our study demonstrates regional specificity including (1) regions with astrocyte activation associated with an increase of GFAP-immunostaining and astrocyte cell counts, together with (2) unaltered GFAP components, and (3) regions characterized by presumably inactive astrocyte with a reduced GFAP-immunostaining. These findings may reflect either different regional alterations in HE, or stages of an alteration progressing differently in different regions.

Regulation of the brain's neuroimmune system is central to development, normal function, and disease. Neuronal communication to microglia, the primary immune cells of the brain, is well known to involve purinergic signaling mediated via ATP secretion and the cytokine fractalkine. Recent evidence shows that neurons release multiple cytokines beyond fractalkine, yet these are less studied and poorly understood. In contrast to ATP, cytokines are a class of signaling molecule that are much larger, with longer signaling and farther diffusion. We posit that neuron-expressed cytokines are an essential mechanism of neuron-microglia communication that arises as part of both normal learning and memory and in response to tissue pathology. Thus, neurons are underappreciated immunomodulatory cells that express diverse immunomodulatory signals. While neuronally sourced cytokines have been understudied, new technical advances make this a timely topic. The goal of this review is to define what is known about the cytokines expressed from neurons, how they are regulated, and the effects of these cytokines on microglia. We delineate key knowledge gaps and needs for new tools to define and analyze neuronal roles in immunomodulation. Given that cytokines are central regulators of microglial function, a broad new body of work is required to illuminate functional links between these neuronally expressed cytokines and sustained and transient microglial function.

The ventral striatum is crucially involved in reward processing. The present study investigates the behavioral effects of astrocyte-specific calcium extrusion virus "CalEx" on perseverative responses in the operant five-choice serial reaction time task and ethanol-conditioned place preference. Mice were injected with CalEx via the GfaABC1D promoter to extrude cytosolic calcium from astrocytes within the ventral striatum. We found that CalEx transfection in the ventral striatum reduced evoked response duration, the maximum amplitude, and the response frequency to 500 μM ATP as measured by ΔF/F fluorescence intensity of the genetically encoded calcium indicator targeting astrocytes GCaMP6f. During the five-choice serial reaction time task, CalEx mice persisted in perseverative responses compared to their counterparts. Additionally, during ethanol-conditioned place preference, CalEx mice showed increased place preference for a low ethanol concentration compared to control group. Furthermore, we found that accumbal astrocytic calcium extrusion increased quinine adulterated ethanol drinking. Our findings suggest that diminishing ventral striatum astrocyte calcium activity contributes to compulsive behaviors, ethanol drinking, and enhanced ethanol drug reward.

The neurogenetic disorder duplication 15q syndrome (Dup15q) is characterized by a high incidence of autism spectrum disorder (ASD) and pharmacoresistant epilepsy. Standard-of-care broad-spectrum anti-seizure medications (ASM) often fail to control seizures in Dup15q, emphasizing the need for the identification of new therapeutic compounds. Previously, we generated a model of Dup15q in Drosophila melanogaster by overexpressing Dube3a in glial cells, instead of neurons. This model recapitulates the spontaneous seizures present in Dup15q patients. Here, we screened a set of FDA-approved compounds for their ability to suppress seizures in repo > Dube3a flies. We used 72 compounds from the Enzo SCREEN-WELL Ion Channel Library for primary screening of seizure suppression. Six compounds were identified that significantly reduced seizure duration. Furthermore, the compounds that passed the primary and secondary screenings were associated with K+ channels. Glial-specific knockdown of the inward rectifying potassium (Irk) 2 channel exacerbated the seizure phenotype in these animals indicating a mechanism of action for drugs that bind irk2, like minoxidil, and can suppress seizures through the rebalancing of K+ extracellularly. This pharmacological and molecular investigation further supports the role of extracellular K+ content in Dup15q seizure activation and provides a putative target for therapeutic intervention.

Neuroglial cells perform numerous physiological functions and contribute to the pathogenesis of all diseases of the nervous system. Neuroglial neuroprotection defines the resilience of the nervous tissue to exo- and endogenous pathological challenges, while neuroglial defence determines the progression and outcome of neurological disorders. IN this paper, we overview previously unknown but recently discovered roles of various types of neuroglial cells in diverse physiological and pathological processes. First, we describe the role of ependymal glia in the regulation of cerebrospinal fluid flow from the spinal cord to peripheral tissues through the spinal nerves. This newly discovered pathway provides a highway for the CNS-body volume transmission. Next, we present the mechanism by which astrocytes control migration and differentiation of oligodendrocyte precursor cells (OPCs). In pre- and early postnatal CNS, OPCs migrate using vasculature (which is yet free from glia limitans perivascularis) as a pathfinder. Newly forming astrocytic perivascular endfeet signal (through semaphorin-plexin cascade) to OPCs that detach from the vessels and start to differentiate into myelinating oligodendrocytes. We continue the astrocyte theme by demonstrating the neuroprotective role of APOE-laden astrocytic extracellular vesicles in neuromyelitis optica. Next, we explore the link between astrocytic morphology and stress-induced depression. We discuss the critical role of astrocytic ezrin, the cytosolic linker defining terminal astrocyte arborisation and resilience to stress: overexpression of ezrin in prefrontal cortical astrocytes makes mice resistant to stress, whereas ezrin knockdown increases animals vulnerability to stress. Subsequently, we highlight the pathophysiological role of oligodendroglial lineage in schizophrenia by describing novel hypertrophied OPCs in the post-mortem patient's tissue and in a mouse model with OPCs overexpressing alternative splice variant DISC1-Δ3. These DISC1-Δ3-OPCs demonstrated overactivated Wnt/β-catenin signalling pathway and were sufficient to trigger pathological behaviours. Finally, we deliberate on the pathological role of astrocytic and microglial connexin 43 hemichannels in Alzheimer's disease and present a new formula of Cx43 hemichannel inhibitor with increased blood-brain barrier penetration and brain retention.

Alzheimer's disease (AD) as a common neurodegenerative disease, which characterized by amyloid Aβ deposition and neurofibrillary tangles. Astragalin (AST), a natural flavonoid, has anti-inflammatory, antioxidant, anti-cancer, and other pharmacological effects. Astrocytes can phagocytize and degrade Aβ in their vicinity. In this study, we used the AD mice model established by injecting the mixture of Aβ1-42 and Aβ25-35 into the CA1 region of the hippocampus, and C8D1A cells injured by Aβ1-42 to explore the neuroprotective effects of AST. Our findings showed that AST enhances learning and cognitive ability of AD mice, reduces Aβ deposition and neurofibrillary tangles in the brain, and improves the structural morphology of hippocampal nerve cells. Furthermore, AST promoted autophagy and suppressed apoptosis of astrocytes in the AD model. Additionally, AST inhibited the expression of proteins associated with the Fas/Fasl-VDAC1 signaling pathway, while autophagy inhibitor chloroquine (CQ) or apoptosis agonist phenoxodiol reversed above change. Interestingly, consistent with the action of pathway Fas inhibitor KR-33493, AST could activate autophagy of Aβ1-42 injured C8D1A cells while inhibit their apoptosis. In conclusion, AST activated autophagy and inhibited apoptosis of hippocampal astrocytes in AD mice, ameliorating animal cognitive deficits by down-regulating Fas/Fasl-VDAC1 signaling pathway. Thus, this study provided a new perspective and experimental foundation for developing AD treatment drugs.

The inherent adaptability of human mesenchymal stromal cells (hMSCs) to differentiate into neural lineages provides a valuable resource for investigating potential neurotoxicity in humans. By harnessing the ability of hMSCs to transform into astrocytes, we can evaluate the effects of various agents on these vital cells. Our protocol employs hMSCs sourced from umbilical cord tissue, ensuring a readily available supply of high-quality cells. The hMSC-to-neural workflow encompasses six essential steps: hMSC culture, followed by the generation of embryoid bodies (EBs) from these cells on specialized surfaces. Next, EBs and cells are expanded in a growth-promoting medium, directing them toward neural lineages. Subsequent differentiation into immature astrocytes is achieved through the use of specific factors. The process continues with the maturation of EBs/cells into astrocyte-like cells (hALCs) under optimized conditions, culminating in the final development of hALCs in a specialized medium. This methodology yields cells that display astrocyte morphology and express characteristic markers such as GFAP and S100β. The protocol is efficient, requiring roughly 6 weeks to generate hALCs from primary hMSCs without genetic manipulation. The application of hMSCs in evaluating cell damage triggered by neurotoxicants like MeHg and MGO underscores their potential as a valuable component within a more extensive battery of neurotoxicity tests.

Cellular senescence contributes to accelerated aging, neuroinflammation, and the development of HIV-associated neurocognitive disorders (HAND) in the era of combined antiretroviral therapy (cART). One HIV viral factor that could lead to cellular senescence is the persistence of HIV-1 Tat in the brain. As a secreted viral protein, Tat is known to enter endolysosomes of cells through receptor-mediated endocytosis, and we have shown that Tat induces endolysosome damage and dysfunction. Significantly, endolysosome dysfunction has been strongly linked to cellular senescence. However, it is not known whether endolysosome dysfunction represents a driver or consequence of cellular senescence. Because Tat-induced endolysosome damage represents an early step in exogenous Tat-induced cellular senescence, we tested the hypothesis that Tat induces cellular senescence via an endolysosome-dependent mechanism in human astrocytes. We demonstrated that Tat interacts with an endolysosome-resident Toll-like receptor 7 (TLR7) via its arginine-rich basic domain, and such an interaction results in endolysosome damage and the development of a senescence-like phenotype including cell cycle arrest, enhanced SA-β-gal activity, and increased release of senescence-associated secretory phenotype (SASP) factors (IL-6, IL-8, and CCL2). Thus, our finding provided mechanistic insights whereby Tat induces endolysosome damage and cellular senescence in human astrocytes. We provide compelling evidence that endolysosome damage drives the development of cellular senescence. Our findings also highlight the novel role of TLR7 in the development of cellular senescence and suggest that TLR7 represents a novel therapeutic target against senescence and the development of HAND.

Astrocytes are highly complex cells that mediate critical roles in synapse formation and maintenance by establishing thousands of direct contacts with synapses through their perisynaptic processes. Here, we found that the most common Parkinsonism gene mutation, LRRK2 G2019S, enhances the phosphorylation of the ERM proteins (Ezrin, Radixin, and Moesin), components of the perisynaptic astrocyte processes in a subset of cortical astrocytes. The ERM hyperphosphorylation was accompanied by decreased astrocyte morphological complexity and reduced excitatory synapse density and function. Dampening ERM phosphorylation levels in LRRK2 G2019S mouse astrocytes restored both their morphology and the excitatory synapse density in the anterior cingulate cortex. To determine how LRRK2 mutation impacts Ezrin interactome, we used an in vivo BioID proteomic approach, and we found that astrocytic Ezrin interacts with Atg7, a master regulator of autophagy. The Ezrin/Atg7 interaction is inhibited by Ezrin phosphorylation, thus diminished in LRRK2 G2019S astrocytes. Importantly, the Atg7 function is required to maintain proper astrocyte morphology. Our data provide a molecular pathway through which the LRRK2 G2019S mutation alters astrocyte morphology and synaptic density in a brain-region-specific manner.

Lipid droplets (LDs) are crucial for energy homeostasis, but are also involved in a wide spectrum of other cellular processes. Accumulating data identifies LDs as an important player in inflammation. However, the underlying mechanisms and the impact of LDs on neuroinflammation remain unclear. Here, we describe a novel function of LDs in human astrocytes, in the context of Alzheimer's disease (AD). Although, the overall lipid profile was unchanged in astrocytes with AD pathology, our data show a clear effect on LD metabolism and specific fatty acids involved in neuroinflammation. Importantly, we found astrocytes to be in close contact with infiltrating CD4 + T cells in the AD brain. Moreover, PLIN3 + LDs in astrocytes co-localize with major histocompatibility complex II (MHCII), indicating a role of LDs in adaptive immunity. Comprehensive analysis of human induced pluripotent stem cell (hiPSC)-derived astrocytes revealed that MHCII is in fact loaded within PLIN3 + LDs and forwarded to neighboring cells via tunneling nanotubes and secretion. Notably, the MHCII molecules are cleaved into its active form prior to packing, indicating an alternative route of MHCII shuttling through LDs, transporting functional immune complexes between cells. Quantification of PLIN3 + LDs in astrocytic cultures, human brain tissue and cerebral organoids indicates that AD pathology initially stimulates PLIN3 + LD formation, but in the long-run results in PLIN3 + LD consumption, which may have consequences on the astrocytes' MHCII distribution capacity. Taken together, our findings present a novel function of PLIN3 + LDs that can be of relevance for AD and other inflammatory conditions.

Progressive neuronal loss is a hallmark of neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, and Amyotrophic Lateral Sclerosis (ALS), which cause cognitive and motor impairment. Delaying the onset and course of symptoms is largely dependent on neuroadaptation, the brain's ability to restructure in response to damage. The molecular, cellular, and systemic processes that underlie neuroadaptation are examined in this study. These mechanisms include gliosis, neurogenesis, synaptic plasticity, and changes in neurotrophic factors. Axonal sprouting, dendritic remodelling, and compensatory alterations in neurotransmitter systems are important adaptations observed in NDDs; nevertheless, these processes may shift to maladaptive plasticity, which would aid in the advancement of the illness. Amyloid and tau pathology-induced synaptic alterations in Alzheimer's disease emphasize compensatory network reconfiguration. Dopamine depletion causes a major remodelling of the basal ganglia in Parkinson's disease, and non-dopaminergic systems compensate. Both ALS and Huntington's disease rely on motor circuit rearrangement and transcriptional dysregulation to slow down functional deterioration. Neuroadaptation is, however, constrained by oxidative stress, compromised autophagy, and neuroinflammation, particularly in elderly populations. The goal of emerging therapy strategies is to improve neuroadaptation by pharmacologically modifying neurotrophic factors, neuroinflammation, and synaptic plasticity. Neurostimulation, cognitive training, and physical rehabilitation are instances of non-pharmacological therapies that support neuroplasticity. Restoring compensating systems may be possible with the use of stem cell techniques and new gene treatments. The goal of future research is to combine biomarkers and individualized medicines to maximize neuroadaptive responses and decrease the course of illness. In order to reduce neurodegeneration and enhance patient outcomes, this review highlights the dual function of neuroadaptation in NDDs and its potential as a therapeutic target.

BackgroundAlzheimer's disease (AD) is characterized by cortical atrophy, glutamatergic neuron loss, and cognitive decline. However, large-scale quantitative assessments of cellular changes during AD pathology remain scarce.ObjectiveThis study aims to integrate single-nuclei sequencing data from the Seattle Alzheimer's Disease Cortical Atlas (SEA-AD) with spatial transcriptomics to quantify cellular changes in the prefrontal cortex and temporal gyrus, regions vulnerable to AD neuropathological changes (ADNC).MethodsWe mapped differentially expressed genes (DEGs) and analyzed their interactions with pathological factors such as APOE expression and Lewy bodies. Cellular proportions were assessed, focusing on neurons, glial cells, and immune cells.ResultsRORB-expressing L4-like neurons, though vulnerable to ADNC, exhibited stable cell numbers throughout disease progression. In contrast, astrocytes displayed increased reactivity, with upregulated cytokine signaling and oxidative stress responses, suggesting a role in neuroinflammation. A reduction in synaptic maintenance pathways indicated a decline in astrocytic support functions. Microglia showed heightened immune surveillance and phagocytic activity, indicating their role in maintaining cortical homeostasis.ConclusionsThe study underscores the critical roles of glial cells, particularly astrocytes and microglia, in AD progression. These findings contribute to a better understanding of cellular dynamics and may inform therapeutic strategies targeting glial cell function in AD.

Epilepsy encompasses a group of chronic brain disorders characterized by recurrent, hypersynchronous activity of neuronal clusters, with epileptic seizures being the primary manifestation of these disorders. The objective of epilepsy treatment is to prevent seizures with minimum adverse side effects. However, approximately 30 % of patients do not respond to available medications. One proposed mechanism of epileptogenesis is glutamate excitotoxicity. When released in excess or not appropriately removed from the synaptic cleft, glutamate hyperactivates receptors, causing a biochemical cascade, which culminates in seizures and cell death. The use of animal models is essential for uncovering potential epileptogenic pathways, understanding the role of receptors and transporters in excitotoxicity, and screening effective antiepileptic treatments. This review examines studies that investigate the role of glutamate transporters and receptors in excitotoxicity and epileptogenesis using animal models. For this, we searched through both PubMed/Medline and ScienceDirect databases. After applying the inclusion and exclusion criteria, 26 (twenty-six) studies were selected for analysis. The studies addressed key glutamate transporter family of excitatory amino acid transporters (EAATs) EAAT1, EAAT2, and EAAT3, responsible for glutamate clearance, as well as AMPA receptor subunits GluA1 and GluA2, NMDA receptor subunits GluN1, GluN2a, and GluN2b, and the metabotropic receptors mGluR5 and mGluR2/3. Results showed that the dysregulation of these transporters and receptors is associated to seizure induction and excitotoxic damage, pointing to their fundamental role in the mechanisms of excitotoxicity and epileptogenesis. These findings highlight the potential of targeting glutamate transporters and receptors to stabilize glutamate homeostasis as an intervention in epilepsy management.

Multiple sclerosis (MS) is a chronic, immune-mediated disease that affects young adults, leading to neurological disability. Regardless of the studies and the research involved in developing an efficient disease-modifying therapy (DMT), relapsing-remitting multiple sclerosis (RRMS) will transition to a progressive multiple sclerosis phenotype. The moment of transition from RRMS to secondary progressive multiple sclerosis (SPMS) is difficult to predict, and the diagnosis is based on the accumulation of disabilities in the evolution of the disease. Research on microRNAs' (miRNAs) role in MS began in the early 2000s, with miR-155 frequently cited for its link to blood-brain barrier dysfunction and neurodegeneration, making it an early transition biomarker from RRMS to SPMS. The purpose of this review is to reveal the importance of finding a biomarker from the molecular field that will be able to identify the transition phase so patients can receive high-efficacy treatments and to cease the clinical progression.

High urea can induce depression and anxiety. Activation of astrocytes is closely associated with psychiatric disorders. However, the pathological mechanism of whether high urea affects astrocyte structure and function to induce anxiety-like behaviors remain unclear. We established a high-urea chronic kidney disease (CKD) mouse model and found that these mice exhibited elevated levels of anxiety through behavioral experiments. Immunofluorescence and transmission electron microscopy studies of astrocytes revealed a decrease in density and branching of mPFC astrocytes. Additionally, we observed a significant reduction in ATP and BDNF levels in the mPFC and primary astrocytes of CKD mice induced by high urea. Analysis of gene expression differences in astrocytes between WT and high-urea mice indicated alterations in mitochondrial dynamics-related signaling pathways in astrocytes. We established a high-urea primary astrocyte model to assess mitochondrial function and levels of fusion and fission proteins. Treatment of primary astrocytes with high urea led to mitochondrial fragmentation and downregulation of Mfn2 expression. These results suggested that high urea downregulates Mfn2 expression in mPFC astrocytes, induced mitochondrial fusion-fission abnormalities, disrupted astrocyte energy metabolism, and promoted high-urea-related anxiety. Mfn2 may represent a potential therapeutic target for high-urea-related anxiety.

This review provides a comprehensive overview of hereditary spastic paraplegias (HSPs) and summarizes the recent progress on the role of glial cells in the pathogenesis of HSPs. HSPs are a heterogeneous group of neurogenetic diseases characterized by axonal degeneration of cortical motor neurons, leading to muscle weakness and atrophy. Though the contribution of glial cells, especially astrocytes, to the progression of other motor neuron diseases like amyotrophic lateral sclerosis (ALS) is well documented, the role of glial cells and the interaction between neurons and astrocytes in HSP remained unknown until recently. Using human pluripotent stem cell-based models of HSPs, a study reported impaired lipid metabolisms and reduced size of lipid droplets in HSP astrocytes. Moreover, targeting lipid dysfunction in astrocytes rescues axonal degeneration of HSP cortical neurons, demonstrating a non-cell-autonomous mechanism in axonal deficits of HSP neurons. In addition to astrocytes, recent studies revealed dysfunctions in HSP patient pluripotent stem cell-derived microglial cells. Increased microgliosis and pro-inflammation factors were also observed in HSP patients' samples, pointing to an exciting role of innate immunity and microglia in HSP. Building upon these recent studies, further investigation of the detailed molecular mechanism and the interplay between glial cell dysfunction and neuronal degeneration in HSP by combining human stem cell models, animal models, and patient samples will open avenues for identifying new therapeutic targets and strategies for HSP.

Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disorder that predominantly affects the elderly. Characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles, AD leads to memory loss, cognitive decline, and severe behavioral changes. As the most common form of dementia, AD imposes a significant global health burden, highlighting the need for interventions that address underlying disease mechanisms rather than only symptomatic treatment. Glial cells, including microglia and astrocytes, play a crucial role in AD progression by mediating neuroinflammatory responses and modulating Aβ clearance and neuronal health. Dysfunction in these cells can exacerbate neuroinflammation and neuronal damage, making glial cells an important target for therapeutic intervention. This review synthesizes findings from in vivo and in vitro studies on melatonin's effects on glial cell dysfunction in AD, emphasizing the multi-mechanistic nature of its neuroprotective properties. Recent studies highlight melatonin's potential as a therapeutic agent that addresses AD-related mechanisms through its interactions with glial cells. Melatonin has demonstrated protective effects, including reducing oxidative stress, apoptosis, and inflammation, inhibiting Aβ fibrillogenesis, and modulating amyloid precursor proteins. Additionally, its influence on glial cell activity, through melatonin receptor pathways, suggests it can alleviate neuroinflammation, a key component of AD progression. The collective evidence points to melatonin's promise as a therapeutic tool with potential roles in both preventive and adjunctive treatments for AD. However, further research is necessary to establish its efficacy and safety in clinical settings.

Dependence is a hallmark of alcohol use disorder characterized by excessive alcohol intake and withdrawal symptoms. The central nucleus of the amygdala (CeA) is a key brain structure underlying the synaptic and behavioral consequences of ethanol dependence. While accumulating evidence suggests that astrocytes regulate synaptic transmission and behavior, there is a limited understanding of the role astrocytes play in ethanol dependence. The present study used a combination of viral labeling, super resolution confocal microscopy, 3D image analysis, and slice electrophysiology to determine the effects of chronic intermittent ethanol (CIE) exposure on astrocyte plasticity in the CeA. During withdrawal from CIE exposure, we observed increased GABA transmission, an upregulation in astrocytic GAT3 levels, and an increased proximity of astrocyte processes near CeA synapses. Furthermore, GAT3 levels and synaptic proximity were positively associated with voluntary ethanol drinking in dependent rats. Slice electrophysiology confirmed that the upregulation in astrocytic GAT3 levels was functional, as CIE exposure unmasked a GAT3-sensitive tonic GABA current in the CeA. A causal role for astrocytic GAT3 in ethanol dependence was assessed using viral-mediated GAT3 overexpression and knockdown approaches. However, GAT3 knockdown or overexpression had no effect on somatic withdrawal symptoms, dependence-escalated ethanol intake, aversion-resistant drinking, or post-dependent ethanol drinking in male or female rats. Moreover, intra-CeA pharmacological inhibition of GAT3 did not alter dependent ethanol drinking. Together, these findings indicate that ethanol dependence induces GABAergic dysregulation and astrocyte plasticity in the CeA. However, these changes in astrocytic GAT3 do not appear to be necessary for the drinking related phenotypes associated with dependence.

Brain abscess is a serious, life-threatening intracranial infection caused by inflammation and collection of infected material. Given the rise of multi-drug resistant strains and the widespread presence of bacteria, it is probable that the incidence of brain abscesses is expected to endure. The sequela of brain abscess constitutes a major source of morbidity and mortality. Brain abscess may cause permanent neurological damage, such as paresis, hydrocephalus, spasticity, mental deterioration and epileptic seizure. Current therapeutic approaches include surgical excision or drainage combined with prolonged antimicrobial treatment usually lasting 6-8 weeks. However, extended antimicrobial treatment may cause adverse side effects, such as nephrotoxicity, ototoxicity, and bone marrow suppression. As a result, it is essential to develop a novel approach to facilitate antibiotics delivery and shorten the therapeutic course clinically. Recently, focused ultrasound (FUS) has been demonstrated to have an ability to temporally open the brain blood barrier (BBB) and modulate the immune response in the brain tumor animal model or in naïve animals. In our study, we demonstrated the focused ultrasound treatment (3W acoustic power, 0.6 MPa peak negative pressure) to treat brain abscess by boosting immune response in CNS infection in the brain abscess animal model. The size of the brain abscess is reduced by 50 percent when the MRI scan is taken at 3 weeks post-treatment. The animals get better recovery after treatment. The use of low intensity FUS with systemic microbubble infusion to open the BBB by mechanical acoustic cavitation elicited an immediate immune response including elevations in proinflmmatory cytokine (IL-1, TNFα and IL-6) in the brain parenchyma surround the brain abscess. Furthermore, FUS exposure treatment also activated glial cells, potentially enhancing the encapsulation of brain abscesses and reducing the spread of bacteria to the adjacent brain parenchyma. Histological analysis also demonstrated that FUS can reduce neuron loss and blood vessel damage during brain abscess formation. Our findings indicate that the FUS system can achieve local reversible BBB opening, enhancing immunomodulation in an animal model of brain abscess.

This study aims to retrospectively compare two resuscitation methods (extracorporeal cardiopulmonary resuscitation (ECPR) vs. emergency preservation and resuscitation (EPR)) by pathohistologically assessing pig brains in a ventricular fibrillation cardiac arrest (VFCA) model. In prospective studies from 2004 to 2006, swine underwent VFCA for 13 (n = 6), 15 (n = 14) or 17 (n = 6) minutes with ECPR (ECPR13, ECPR15 and ECPR17). Another 15 min VFCA group (n = 8) was resuscitated with EPR and chest compressions (EPR15 + CC). Brains of animals surviving for nine days (ECPR13 n = 4, ECPR15 n = 2, ECPR17 n = 1, EPR15 + CC n = 7) were harvested. Eight different brain regions were analyzed with the image analysis software QuPath using HE-staining, GFAP- and Iba1-immunohistochemistry. Only ECPR13 and EPR15 + CC animals were included in statistical analysis, due to low survival rates in the other groups. All VFCA samples showed significantly fewer viable neurons compared to shams, but no significant differences between ECPR13 and EPR15 + CC animals were observed. ECPR13 animals showed significantly more glial activation in all cerebral cortex regions compared to shams and in occipital, temporal and parietal cortex compared to EPR15 + CC. In conclusion, EPR + CC resulted in a significantly reduced inflammatory reaction in cerebral cortex compared to ECPR but did not influence the extent of neuronal death after VFCA.

Intracranial pressure (ICP) is pressure within the cranium, between 5 and 15 mmHg in a normal brain, and is influenced by the dynamic balance between brain tissue, cerebrospinal fluid (CSF) and cerebral blood volume. ICP is vital for cerebral health, impacting outcomes in various neurological conditions. Disruptions, such as cerebral haemorrhage, hydrocephalus and malignant hypertension, can lead to elevated ICP, a dangerous condition known as intracranial hypertension (IH). Systemic hypertension significantly impacts cerebral health by causing microvascular damage, dysfunction of the blood-brain barrier (BBB) and impairment of intracranial compliance (ICC). This increases the risk of IH), cerebral ischaemia, neuroinflammation and lacunar infarction, further worsening neurological dysfunction. This review describes the complex relationship between hypertension and ICP regulation, focusing on the mechanisms underlying ICP and ICC adjustments in hypertensive conditions and emphasizing the role of BBB integrity and cerebral blood flow (CBF) dynamics. It discusses how the sympathetic output might change the regulation of CBF and the maintenance of ICP, highlighting how hypertensive conditions can impair this mechanism, increasing the risk of cerebral ischaemia. The neurovascular unit, including astrocytes and microglia, plays a significant role in this process, contributing to IH in hypertensive patients. Understanding the effects of hypertension on ICP and ICC could lead to therapies aimed at preserving BBB integrity, reducing inflammation and improving cerebral compliance, potentially preventing brain dysfunction and reducing stroke risk in hypertensive patients. This review underscores the need for early detection and intervention to mitigate the severe consequences of uncontrolled hypertension on cerebral health.

The inability of damaged neurons to regenerate and of axons to establish new functional connections leads to permanent functional deficits after spinal cord injury (SCI). Although astrocyte reprogramming holds promise for neurorepair in various disease models, it is not sufficient on its own to achieve significant functional recovery.

A rat SCI model was established using a spinal cord impactor. Seven days postsurgery, adeno-associated virus were injected to overexpress the transcription factors NeuroD1 and Neurogenin-2 (Ngn2) in the spinal cord. The rats were then trained to walk on a weight-supported treadmill for 4 weeks, starting 14 days after modeling. The effects of these interventions on motor and sensory functions, as well as spinal cord tissue repair, were subsequently evaluated.

The combination of NeuroD1 and Ngn2 overexpression with weight-supported exercise training significantly improved gait compared to either intervention alone. The group receiving the combined intervention exhibited enhanced sensitivity in sensory assessments. Immunofluorescence analysis revealed increased colocalization of astrocytes and microtubule-associated protein 2-positive neurons in the injury area. These effects were more pronounced than those observed with spinal cord tissue repair alone. Additionally, the combined intervention significantly reduced glial scarring and the size of the injury area.

Exercise intervention enhances the reprogramming effects of astrocytes and restores motor function, yielding better results than either intervention alone.

Epileptology - with epilepsy as one of the most common neurological diseases - has an urgent need for easily accessible biomarkers to improve diagnosis, prognosis and therapeutic monitoring. Neurofilament light chain (NfL) and Glial Fibrillary Acidic Protein (GFAP) have emerged as promising fluid biomarkers in various neurological disorders. Their potential role in epileptic seizures and epilepsy remains largely unexplored. To assess the current state of research on this topic we comprehensively searched the published literature for studies on GFAP and/or NfL in cerebrospinal fluid and/or blood in adult humans with epileptic seizures, status epilepticus or epilepsy (last data base search on 10th of May 2024). We identified a total of 2285 publications of which 19 fulfilled our search criteria. The studies targeted various outcomes such as prognosis in status epilepticus, differentiation of seizure semiology and etiology, differentiation of epileptic seizures from non-epileptic conditions, prediction of epilepsy in autoimmune epilepsy, after a stroke or after a first unprovoked seizure, the role of the time interval from seizure to sampling, the association with disease duration as well as seizure frequency and the influence of seizure suppressing medication. The results are heterogeneous but indicate promising applications for both NfL and GFAP in diagnosis and prognostication of patients with epileptic seizures and epilepsy. In the present review we summarize the current evidence, future perspectives, but also limitations, of NfL and GFAP as fluid biomarkers in epilepsy and epileptic seizures.

Astrocytes and oligodendrocytes, once considered passive support cells, are now recognized as active participants in the pathogenesis of Alzheimer's disease. Emerging evidence highlights the critical role that these glial cells play in the pathological features of Alzheimer's, including neuroinflammation, excitotoxicity, synaptic dysfunction, and myelin degeneration, which contribute to neurodegeneration and cognitive decline. Here, we review the current understanding of astrocyte and oligodendrocyte pathology in Alzheimer's disease and highlight research that supports the therapeutic potential of modulating astrocyte and oligodendrocyte functions to treat Alzheimer's disease.