Search Results (265)

Huntington’s disease (HD) has traditionally been conceptualized as a neuron-centric disorder primarily attributed to cell-autonomous toxicity of mutant huntingtin (mHTT) in striatal medium spiny neurons. However, this framework inadequately explains the prolonged presymptomatic phase, selective network vulnerability, early non-motor manifestations, and limited success of neuron-targeted therapeutic interventions. Accumulating evidence from molecular biology, transcriptomics, neuroimaging, and preclinical therapeutics supports a reframing of HD as a disorder of neuroglial systems dysfunction. We synthesize data demonstrating that astrocytes, microglia, and oligodendrocyte lineage cells are not passive bystanders but play direct and interactive roles in HD pathogenesis through defined molecular mechanisms. Expression of mHTT in glial populations impairs synaptic homeostasis, metabolic coupling, immune resolution, and myelin integrity, generating self-amplifying pathological feedback loops that destabilize neural circuits long before overt neuronal death. Critically, we evaluate glial replacement therapy as a potential disease-modifying strategy. Preclinical studies demonstrate that transplantation of healthy human glial progenitor cells substantially ameliorates motor, cognitive, and neuropathological deficits in multiple HD models through oligodendroglial remyelination and lactate-mediated metabolic support, despite persistent neuronal mHTT expression. Effective HD therapy will likely require strategies that jointly target the genetic cause and the dysfunctional neuroglial microenvironment. By integrating systems neuroscience with glial biology and translational strategy, this review defines a neuroglial framework for HD that opens a plausible path toward meaningful disease modification and positions HD as a model disorder for glial-centric interventions in neurodegeneration. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder traditionally characterized by the extracellular accumulation of amyloid-beta (Abeta) plaques and the formation of intracellular neurofibrillary tau tangles; however, the prevailing scientific paradigm has shifted toward an integrative model of pathogenesis that recognizes neuroinflammation as a critical, self-perpetuating driver of cognitive attrition. This multifaceted interplay is mediated by the brain–body axis, wherein chronic systemic inflammation—stemming from metabolic dysfunction, cardiovascular disease, or environmental stressors such as fine particulate matter PM_2.5—compromises the structural integrity of the blood–brain barrier. Such environmental insults serve as priming agents for the innate immune system, shifting peripheral immune populations toward a pro-inflammatory phenotype that is further exacerbated by the stabilization of hypoxia-inducible factors (HIFs) through oxidative stress-induced pseudohypoxia, even under normoxic conditions. The subsequent activation of microglia and astrocytes transitions the cerebral microenvironment from a homeostatic, neurosupportive state into a neurotoxic milieu that actively promotes synaptic loss and neuronal death. Consequently, contemporary research has pivoted from broad-spectrum anti-inflammatory interventions toward targeted immune modulation, emphasizing that a comprehensive understanding of how systemic dysfunction perpetuates neuroinflammatory cascades is essential for developing efficacious therapies capable of attenuating AD progression and mitigating its global health burden. Full article

Vitamin D has long been recognized for its role in calcium homeostasis and bone metabolism; however, it is now emerging as an important regulator of central nervous system (CNS) function. Recent evidence suggests that vitamin D signaling contributes to the pathogenesis and progression of several neurodegenerative disorders. Vitamin D exerts neuroprotective effects through multiple mechanisms, including regulation of calcium homeostasis, modulation of immune responses, reduction in oxidative stress, stimulation of neurotrophic factors, and maintenance of blood–brain barrier (BBB) integrity. Vitamin D receptors and metabolizing enzymes are widely distributed across several brain regions, highlighting their direct involvement in neuronal function. This review summarizes the biosynthesis, metabolism, and signaling pathways of vitamin D. It explores its role in neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, and traumatic brain injury (TBI). Evidence from experimental and clinical studies indicates that vitamin D deficiency is associated with an increased risk and severity of these conditions, while supplementation may provide therapeutic benefits. Full article

Severe Combined Immunodeficiency (SCID), Spinal Muscular Atrophy (SMA), and X-Linked Agammaglobulinemia (XLA) are rare but life-threatening genetic disorders in infants that can lead to severe infections, progressive neuromuscular degeneration, or severe immune dysfunction associated with significant morbidity and mortality if not diagnosed early. Advances in newborn screening (NBS) technologies have enabled pre-symptomatic detection of these conditions, allowing early initiation of life-saving interventions such as hematopoietic stem cell transplantation, gene therapy, and immunoglobulin replacement therapy. However, the absence of a standardized national clinical pathway linking screening, confirmatory testing, and specialist referral in Malaysia continues to contribute to delayed diagnosis and suboptimal patient outcomes. This review examines and synthesizes current evidence on the clinical pathways for early diagnosis and management of SCID, SMA, and XLA, with particular emphasis on diagnostic workflows, screening technologies, and healthcare system challenges within the Malaysian context. The review examines disease epidemiology, consequences of delayed diagnosis, and the role of expanded NBS under the Screening for Health, Intervention, Nurturing of Every Child (SHINE) program in improving early diagnosis and management. In addition, the paper outlines the current NBS landscape, the use of multiplex real-time polymerase chain reaction (PCR) assays for simultaneous detection of T-cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and survival motor neuron 1 (SMN1) gene deletion of exon 7 from dried blood spot (DBS) samples. A structured diagnostic framework incorporating screening interpretation, confirmatory testing, and urgency-based referral pathways is also proposed. By addressing current operational barriers and coordinating laboratory referral systems, expanding NBS programs could significantly improve early diagnosis and long-term outcomes for infants affected by SCID, SMA, and XLA in Malaysia. Full article

Equine asthma is a chronic inflammatory disease of the lower respiratory tract, primarily associated with inhalation of organic dust, microbial particles and environmental aeroantigens. Although the inflammatory and immunological mechanisms underlying equine asthma have been extensively investigated, the potential contribution of neuroimmune pathways remains poorly understood. In humans and rodent models, asthma is increasingly recognised as a disorder involving complex bidirectional interactions between the nervous and immune systems. Sensory nerve activation, neuropeptide release, autonomic dysregulation and neuronal remodelling contribute to bronchoconstriction, airway hyperresponsiveness, mucus hypersecretion and chronic airway remodelling. This review summarises current knowledge of the neuroimmune mechanisms involved in asthma, with particular emphasis on comparative aspects across humans, rodents and horses. Literature searches were conducted using the PubMed database, focusing on studies investigating neurogenic inflammation, airway innervation, neuropeptides, transient receptor potential channels and neuronal remodelling in asthma and chronic airway disease. Existing equine evidence indicates the presence of substance P- and calcitonin gene-related peptide-immunoreactive nerve fibres in the equine airways, increased neurokinin-mediated bronchoconstriction in severe equine asthma, and enhanced airway innervation in affected horses. However, compared with human and rodent studies, horse-specific data remain extremely limited. Current evidence suggests that neuroimmune pathways are unlikely to be the primary initiating mechanism of equine asthma, but may act as important modulators of chronic airway dysfunction and disease progression. The marked scarcity of equine studies investigating neuroimmune signalling represents a major knowledge gap and highlights an important direction for future research in equine respiratory medicine. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) and the accumulation of tau in the brain, which triggers robust innate immune responses. Growing evidence indicates that neuroinflammation contributes to AD progression by overactivating microglia through the release of cytokines and chemokines. In general, chemokines can disrupt neuronal communication and promote blood–brain barrier permeability. Peripheral immune cells are mobilized into the brain by a gradient of chemokines. These processes link peripheral immune responses with substantial T-cell infiltration into the CNS parenchyma, leptomeninges and cerebrospinal fluid of both AD mice and AD patients. This finding underscores the relevance of the adaptive immune system, particularly T and B cells, in AD neuropathology. T-cell infiltration into the brain can influence amyloid clearance through chemokine signalling. However, chemokines play a critical role in AD by either promoting or suppressing disease progression. The infiltration of peripheral T and B cells into the brain parenchyma can exacerbate neuronal loss, yet it may also exert neuroprotective effects. Despite the presence of CD4⁺ and CD8⁺ T cells in postmortem brains of AD patients, debate continues about their role in AD brains, in terms of whether they are protective or detrimental. Understanding the complex role of chemokines in controlling innate and adaptive immune responses by modulating neuron–glia interactions (involving astrocytes and microglia) may provide novel therapeutic approaches for AD. Targeting chemokine signalling or treating with drugs that can prevent the recruitment of immune cells may be promising strategies for treating AD neuropathology. Therapies that prevent the overactivation of T cells in the brain could lead to protective strategies against AD. In fact, regulatory T cells (Tregs) could delay the onset of cognitive symptoms, because they suppress inflammation and slow the accumulation of Aβ plaques and p-Tau in the brain. Complementary strategies, such as photobiomodulation, nanoparticle, and T-cell-based approaches, could mitigate AD progression in patients. Full article

Human herpesvirus-6 consists of a pair of viral species, HHV-6A and HHV-6B, which are neurotropic with the ability to invade, persist, and reactivate within the nervous system. Accumulating evidence links HHV-6 to epilepsy and other neuropathologies, including: multiple sclerosis, chronic fatigue syndrome, and neurodegeneration. Yet, mechanisms by which these viruses induce neurological disorders, including their role in epileptogenesis, remain unknown. It has been demonstrated that HHV-6 exhibits tropism for astrocytes, oligodendrocytes, and neurons. Thus, HHV-6 can perturb cellular homeostasis, neuronal signaling, and immune regulation, astrocytic glutamate clearance, GABAergic inhibition, and cholinergic or monoaminergic neurotransmission yielding network hyperexcitability. It is also reported that HHV-6 can activate neuroinflammation through Toll-Like Receptor (TLR), cytokine, and/or NF-$\kappa$B activation, which facilitates neuronal injury and network instability. Indeed, a suite of converging processes suggest a multifactorial nature for HHV-6 related neuropathology. Despite robust experimental and clinical data, definitive causal relationships between HHV-6 and epilepsy (or induction of neurodegeneration) remain elusive. This review discusses evidence for roseolovirus-induced neurological dysfunction and disorders commonly associated with HHV-6A and HHV-6B infections. A preponderance of clinical and experimental evidence suggests that differential tropism for distinct neuronal neurotransmitter chemotypes and glia as well as systemic effects are involved in roseolovirus-mediated neurological disease. Full article

Visceral pain is a central feature of chronic gastrointestinal disorders, yet the epithelial sensory mechanisms that shape afferent input before it enters pain-relevant neural pathways remain insufficiently integrated into current models. This review advances the concept that the intestinal epithelium is not only a barrier or endocrine interface, but also an active neuroepithelial regulatory layer positioned upstream of visceral sensory signaling. Neuropod-cell studies established that specialized epithelial cells can communicate rapidly with vagal neurons and preserve luminal stimulus identity through transmitter-selective coding. Enterochromaffin cells extend this framework as polymodal epithelial sensory transducers that detect chemical, microbial, neurohumoral, and mechanical cues, convert them into serotonergic afferent signaling, and can causally amplify visceral hypersensitivity in experimental models. Complementing these amplifying pathways, GUCY2C^high (guanylate cyclase C-enriched) neuropod-like epithelial cells reveal a pain-restraining mechanism that regulates dorsal root ganglion excitability and preserves linaclotide-responsive suppression of nociceptive output in preclinical systems. Together, these findings support an integrative model in which epithelial sensory circuits may act as filters of biological meaning, amplifiers of afferent gain, and brakes on aberrant nociceptive escalation. This framework does not replace neural, immune, or central mechanisms of visceral pain, but adds an upstream epithelial tier that may shape pain vulnerability, persistence, or treatment responsiveness in selected contexts. Defining the cellular logic, molecular mediators, and human relevance of these circuits will be essential for advancing neuroepithelial pain biology toward disease-relevant and therapeutic applications. Full article

Hereditary cerebellar ataxias are progressive neurodegenerative disorders for which disease-modifying treatments remain lacking. Although these conditions have traditionally been investigated from a neuron-centered perspective, evidence from several ataxia models indicates that changes in the cerebellar immune microenvironment can arise before overt neuronal loss and may contribute to early circuit dysfunction. This review examines hereditary cerebellar ataxias through the lens of early neuroimmune regulation, with particular attention to the region-specific properties of cerebellar microglia and their roles in synaptic refinement, inflammatory tone modulation and circuit homeostasis. We further discuss zebrafish as a useful experimental system for this question, because they combine in vivo imaging, genetic manipulation, and scalable functional assays in an intact vertebrate model. In this context, flavonoids—and especially naringenin—are not considered as immediate therapeutic candidates, but as mechanistically informative experimental probes to investigate how modulation of neuroimmune signaling affects disease-relevant phenotypes in vivo. By integrating genetic ataxia models with dynamic neuroimmune readouts, functional behavioral assays, and circuit-level analyses, zebrafish-based approaches can help identify early windows during which neuroimmune signaling influences cerebellar resilience and disease progression and can guide subsequent validation in mammalian systems. Full article

Endotoxemia represents a life-threatening clinical disorder driven by an aberrant host immune response to pathogenic infection, often resulting in severe multiple organ dysfunction. Among its most devastating complications are acute lung injury (ALI) and endotoxemia-associated encephalopathy (EAE), both of which are associated with elevated mortality and currently lack effective targeted interventions. This study evaluated the therapeutic efficacy and underlying molecular mechanisms of recombinant human thymosin β4 (rhTβ4) in a murine model of lipopolysaccharide (LPS)-induced endotoxemia. Our results showed that treatment with rhTβ4 markedly enhanced survival rates and diminished the systemic overproduction of diverse proinflammatory cytokines and chemokines in endotoxemic mice. These systemic protective actions were achieved through the inhibition of the TLR4/NF-κB signaling cascade, the reduction in M1 macrophage polarization, and the simultaneous alleviation of mitochondrial impairment and oxidative stress. Moreover, rhTβ4 treatment significantly rescued EAE-related cognitive deficits and attenuated neuronal damage, primarily through the suppression of neuroinflammation and microglial overactivation. Integrative transcriptomic profiling and functional assays identified lysophosphatidic acid receptor 3 (LPAR3) as an important contributor, suggesting that rhTβ4 suppresses microglial-mediated neurotoxicity at least in part through LPAR3 downregulation. In conclusion, rhTβ4 confers robust multi-organ protection against endotoxemic injury by orchestrating the inhibition of systemic and central neuroinflammatory cascades, positioning it as a promising candidate for the treatment of endotoxemia-induced ALI and EAE. Full article

Multiple Sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system characterized by leukocyte infiltration, inflammation, demyelination, and progressive neurodegeneration. Susceptibility to MS is influenced by genetic factors, including variants within the human leukocyte antigen (HLA) region, (notably HLA-DR15), and multiple single nucleotide polymorphisms that modulate T cell function and immune regulation. Clinically, early manifestations such as visual disturbances, sensory deficits, fatigue, and impaired coordination often precede more advanced features, including cognitive decline and bladder or bowel dysfunction. Although experimental and genetic models of neuroinflammation have facilitated the development of therapies that reduce relapse rates and slow disease progression, the underlying pathological mechanisms remain incompletely understood. Emerging evidence points to the importance of cytoskeletal organization and membrane-associated signaling platforms in maintaining neuronal and immune cell function. Disruption of these systems may contribute to demyelination and neuroinflammatory cascades. Within this context, a systems biology perspective is particularly valuable, as it emphasizes the integration of multiple, interdependent pathways rather than isolated mechanisms. Caveolin-1 (Cav-1), an integral membrane protein of caveolae, has gained attention as a potential central regulator due to its role in coordinating signaling processes across diverse cellular compartments. In this review, we examine the potential genetic and functional contributions of Cav-1 to MS pathophysiology, with a focus on its involvement in oxidative stress, inflammation, blood–brain barrier integrity, and autophagy. By framing these processes as components of an interconnected network, we highlight Cav-1 as a context-dependent modulator that may influence both disease progression and severity. However, despite its mechanistic relevance, the translational potential of Cav-1 remains uncertain, and further studies are required to clarify its precise role and evaluate its suitability as a therapeutic target in MS. Full article

Neurodevelopment is a dynamic and multifactorial process, critical in the early stages of life, involving the formation of neural networks, the establishment of synapses, and the maturation of cognitive, social and emotional circuits. In this context, the gut microbiome emerges as an essential regulator of neurodevelopment, exerting influences through multiple biochemical and immunological mechanisms that define the “gut-brain axis”. The microbiota modulates neurodevelopment by regulating neurotransmitters (serotonin, dopamine, GABA), the production of microbial metabolites, including short-chain fatty acids, the modulation of inflammatory cytokines, and vagal signaling to the central nervous system. Recent evidence highlights the role of microbiota in modulating microglia, synaptogenesis, dendritic maturation, and neuronal plasticity, emphasizing how these processes are influenced by microbial activity rather than providing a comprehensive treatise on plasticity itself. Gut microbiota disturbances, or dysbiosis, have been associated with various neuropsychiatric and neurodevelopmental disorders, contributing to cognitive, behavioral, and emotional dysfunctions. This article summarizes, in a narrative manner, the main dysbiosis patterns identified in these disorders and the biological mechanisms by which the microbiome influences neuronal development and function, including immune–neuronal interactions, metabolomic modulation, and neuroendocrine signaling. Finally, emerging directions of intervention aimed at adjusting the microbial profile, such as dietary adjustment, the use of probiotics, prebiotics, symbiotics, and fecal microbiota transplantation, are presented with the aim of positively influencing neurodevelopment and preventing or ameliorating associated dysfunctions. This review emphasizes the need for longitudinal, rigorous, and controlled clinical trials to validate the efficacy of microbiota modulation strategies and to substantiate their integration into individualized pediatric management protocols. Full article

Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system (CNS) characterized by persistent inflammation, demyelination, and progressive neurodegeneration, driven largely by aberrant activation of T and B lymphocytes that infiltrate the CNS and cause myelin and axonal damage, leading to neurological impairment. Although current therapies broadly suppress immune activity and reduce relapse rates, their effects on neurodegenerative processes remain limited. Also, the safety profile of disease-modifying therapies (DMTs) may become problematic, especially in older patients with comorbidities and/or advanced disability. Emerging data suggest that opioid signaling may exert immunomodulatory, remyelinating, and neuroprotective effects, representing a novel and underexplored therapeutic avenue. Given that current MS therapies primarily target inflammation but fail to promote myelin repair or prevent neurodegeneration, opioid signaling emerges as a novel and underexplored pathway with potential benefits for immunomodulation and remyelination, as well as possible neuroprotective effects. Despite concerns about classical opioid-related adverse effects, accumulating evidence shows that opioid-mediated interventions have been associated with reduced inflammatory activity, attenuation of demyelination, and enhanced neuronal survival and have shown therapeutic benefit in MS. Although current findings are largely preclinical, they provide a compelling rationale for further investigation of the opioid system as a potential adjunctive or novel therapeutic strategy. Full article

Background: Extracellular vesicles (EVs) mediate intercellular communication in the central nervous system and are a major source of biomarkers. This study characterizes the EV-derived proteome secreted by human endothelial brain cells (HEBCs), astrocytes, and neurons to identify cell-specific roles in intercellular communication in the brain. Methods: Mass spectrometry analyses of EVs and corresponding parent cells were performed to identify differentially enriched proteins. Gene Ontology (GO) analysis of statistically significant, abundantly expressed proteins between EVs and parent cells (log₂ fold-change ≥ 2.0, p < 0.05) was performed to assess cell-specific functions. Results: Proteome analysis identified on average 932 proteins in astrocyte EVs (versus 1725 in parent cells), 1040 in HEBC EVs (versus 5451 in parent cells), and 470 in neuronal EVs (versus 578 in parent cells). The analysis indicated that astrocytes had the highest number of significantly abundant proteins (118), followed by HEBCs (24) and neurons (25). Astrocyte EVs were enriched in lipoproteins, complement factors, and protease inhibitors; HEBCs EVs in tight junction proteins, adhesion molecules, and protease regulators; and neuronal EVs in chromatin-associated histones, tubulin isoforms, and RNA-binding proteins. Conclusions: The proteomic signatures of EVs from different neurovascular unit cells suggest specialized roles in blood–brain barrier homeostasis, immune regulation, and synaptic and epigenetic signaling under healthy conditions. These baseline signatures provide a framework for future studies to investigate how brain cell-derived EVs may contribute to neurodegenerative disorders. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and neuropathological hallmarks such as amyloid-β plaques and neurofibrillary tangles. In recent years, chronic neuroinflammation has emerged as a central mechanism linking genetic, metabolic, and immune dysfunctions in AD. Activated microglia and astrocytes release pro-inflammatory cytokines and reactive oxygen species that exacerbate synaptic and neuronal injury, while impaired clearance mechanisms and blood–brain barrier disruption further sustain inflammation. A growing body of research highlights the role of immunometabolism—the bidirectional interaction between immune activation and cellular metabolism—in shaping glial phenotypes and disease progression. Dysregulation of glucose, lipid, and amino acid metabolism, together with alterations in key metabolites such as lactate, NAD⁺, and reactive oxygen species, promotes a maladaptive inflammatory state. Genetic factors including APOE4 and TREM2 variants affect microglial lipid handling pathways, while systemic metabolic disorders and gut microbiota alterations amplify neuroinflammatory cascades. Natural bioactive compounds, particularly polyphenols, have gained attention for their ability to modulate immunometabolic pathways. By activating AMPK and SIRT1 and inhibiting mTOR and NLRP3 inflammasome signaling, polyphenols may tune mitochondrial function, redox homeostasis, and autophagy, promoting adaptation to chronic metabolic stress. Therefore, metabolic-immune interactions represent pleiotropic therapeutic avenues for AD. Understanding how immunometabolites and nutrient-sensing pathways regulate compartmentalized inflammation in the CNS may pave the way for novel interventions that combine metabolic precision with neuroprotective efficacy. Full article