Search Results (84)

B-cell-depleting therapies have revolutionized multiple sclerosis (MS) treatment, yet relapses persist in some patients—suggesting additional pathogenic drivers beyond peripheral B cells. Tertiary lymphoid structures (TLS) are extensively documented in progressive MS at autopsy, but whether their formation begins during the relapsing-remitting phase and how they evolve during the transition to progression remain undefined. Here, using the relapsing-remitting PLP_139–151-induced EAE model, we uncover that TLS-like structures form in the subventricular zone during relapse, once established, persist through remission as niches containing both B cells and persistently activated microglia. Neither B-cell depletion alone nor BTK inhibition alone fully prevents relapse. Strikingly, early combined B-cell depletion and BTK inhibition virtually abolishes TLS-like structure formation and may effectively prevent complete disease relapse in this model. By contrast, late initiation of the same combination fails to resolve existing TLS-like structures or prevent relapse, although it attenuates disease severity. These data indicate that established TLS-like structures may represent treatment-resistant compartments, and that both B cells and microglia may be crucial during early formation for sustaining their disease relapse-driving activity. Our study confirms that TLS-like structures may be a key factor driving the compartmentalization of central nervous system inflammation, points to a potentially narrow therapeutic window for intervention, and proposes that early combined B-cell depletion and BTK inhibition may represent a promising strategy worthy of further investigation. Full article

Obesity is a major risk factor for colorectal cancer (CRC) and is increasingly recognized as a contributor to cancer-related cognitive impairment; however, the mechanistic pathways linking metabolic dysfunction, tumor progression, and brain dysfunction remain incompletely defined. Emerging evidence indicates that obesity-induced gut microbial dysbiosis and intestinal barrier disruption may serve as a biologically plausible mechanism connecting these processes via the gut–brain axis although direct clinical causality remains to be firmly established. In obesity, alterations in gut microbiota composition characterized by depletion of barrier-protective taxa and enrichment of pro-inflammatory and genotoxic pathobionts compromise epithelial tight-junction integrity and promote metabolic endotoxemia. The translocation of microbial products, including lipopolysaccharide, sustains chronic systemic inflammation, accelerates CRC progression, and remodels the tumor microenvironment. Notably, these peripheral inflammatory signals extend beyond the intestine and tumor, disrupting blood–brain barrier integrity, activating microglia and astrocytes, and impairing synaptic plasticity within hippocampal and frontal networks. Clinically, these processes manifest as cancer-related cognitive impairment (CRCI), with predominant deficits in attention, processing speed, and working memory, which are often detectable around the time of diagnosis and independent of chemotherapy exposure. This review synthesizes in vivo, in vitro, and human evidence into a proposed theoretical “two-barrier failure” model of obesity-associated CRC and cognitive dysfunction. In addition to mechanistic synthesis, we discuss barrier-centered therapeutic strategies, including targeted probiotics, postbiotics, SCFA supplementation, obesity management through dietary and weight-loss interventions, and potential pharmacological approaches to epithelial and neurovascular barrier protection. We also outline testable clinical trial designs for evaluating these interventions in obesity-associated CRC. Full article

As an emerging tire wear-derived environmental contaminant, 6PPD-quinone (6PPDQ) has raised significant concerns regarding its neurotoxic potential, particularly for children exposed to recycled tire crumb rubber in playgrounds. However, the molecular mechanisms by which 6PPDQ influences neurological disorders such as epilepsy remain poorly understood. In this study, we employed an integrative framework combining network toxicology, bulk analysis of human epileptic brain tissues, Mendelian randomization, and molecular dynamics simulations to elucidate these mechanisms. Our findings, validated through CETSA-WB and SPR, identify 6PPDQ as a direct ligand that binds to and stabilizes neuronal TP53. Through a synergistic double-hit mechanism, 6PPDQ directly engages the TP53 pathway while simultaneously triggering microglial interleukin-6 secretion. These converging pathways lead to the suppression of the master antioxidant regulator Nrf2, resulting in glutathione depletion, excessive reactive oxygen species accumulation, and exacerbated neuronal damage under excitotoxic stress. Experimental validation using glutamate-induced HT22 cell models and microglia–neuron crosstalk systems confirmed that targeting the TP53/Nrf2 axis or scavenging ROS significantly attenuates 6PPDQ-induced neurotoxicity. Our findings highlight critical risks to pediatric neurological health posed by tire-derived contaminants and identify the TP53/Nrf2 axis as a promising therapeutic target. Furthermore, this work provides a robust scientific basis for refining risk assessment frameworks and developing regulatory strategies to mitigate environmental exposure to 6PPDQ. Full article

The limit of disease-modifying therapeutic strategies against epilepsy has prompted mainstream epilepsy research toward understanding the pathways contributing to epileptic seizures. Microglia, the powerhouse of the brain’s innate immune system, is known for its role in epileptic seizures, contributing via neuroinflammation, neuronal death, and neurogenesis. Therapeutic targeting of microglia with its inhibitor and therapeutic compounds modulating its activation reduces the development of spontaneous recurrent seizure after status epilepticus in a pre-clinical model. Herein, we review various aspects of microglia in epilepsy, including their contribution to seizure-induced neuronal death and neurogenesis, the outcome of depleting microglia (both pharmacologically and genetically), the aspects of microglia–astrocyte interaction, and promising therapeutic outcomes achieved by targeting microglia. Full article

Growing evidence suggests that psychiatric disorders are characterized by a prolonged inflammatory state, which may influence the efficacy of compounds targeting serotonin. Serotonin is a key signaling molecule in neuroplasticity of the adult hippocampus and involved in antidepressant action. Recent in vitro studies indicate the neurotransmitter may also facilitate the response to inflammation and potentially modulate microglial function towards neuroprotection. Using Tph2^−/− rats depleted of brain serotonin, we examined microglial expression of various serotonin receptors (5-HTRs) in vivo in both the hippocampus and prefrontal cortex and assessed mRNA levels of cytokines and brain-derived neurotrophic factor (BDNF). We observed age-dependent and region-specific gene expression of 5-HTRs on sorted microglia, paralleling changes in BDNF signaling, especially with 5-HT2b. Notably, both 5-HT2b and BDNF expression in the hippocampus was significantly upregulated in the absence of brain serotonin. Our data indicate distinct roles of 5-HTR subtypes in early network formation (5-HT1b, 5-HT5b) and in the response to endogenous changes (5-HT2b, 5-HT5a). Understanding serotonin–microglia interplay could offer therapeutic insights into the maintenance of mood via brain–immune cell interactions. Full article

The nuclear kinases mitogen- and stress-activated kinase 1 and 2 (MSK1 and MSK2), through regulating transcriptional processes, are pivotal for various adaptive responses, including inflammation, learning and addiction. Transcriptional alterations in neurons and glia cells within the pain signal-processing (nociceptive) pathway, including the superficial spinal dorsal horn (SSDH), are critical for the development and persistence of inflammatory pain that results from tissue injuries and subsequent inflammatory reactions. While previous reports have indicated that MSK1 contributes to transcriptional changes in inflamed tissues, the impact of MSK1 on nociceptive processing in the SSDH are poorly understood at present. Here, we report MSK1 immunoreactivity (IR) in a group of excitatory and inhibitory neurons as well as in microglia and oligodendrocytes in the SSDH. Injecting Complete Freund’s Adjuvant into the mouse hind paw produced robust non-evoked pain-related behavior, which was significantly attenuated by global depletion of MSK1. In wild-type mice, the inflammatory pain was accompanied by transient MSK1-dependent phosphorylation of the MSK1 downstream effector histone 3 at serine 10 at one hour but not two days after the injection; still, the number of nuclei exhibiting activated MSK1 expression remained highly restricted even at 1 h post-injection. Our data indicate that MSK1 contributes to inflammatory pain via epigenetic and transcriptional alterations; however, once initiated, MSK1’s downstream effects do not require further drive from the persistent activity of the MSK1 signaling pathway in the SSDH. Full article

Background: Focal cortical dysplasia (FCD) is a prevalent cause of drug-resistant epilepsy, but a comprehensive understanding of its pathogenesis at a cellular resolution remains limited. Previous transcriptomic studies, often constrained by bulk tissue analysis, have been unable to dissect the cell-type-specific contributions to epileptogenesis. Methods: We performed scRNA-seq on cortical tissues from one surgical patient with FCD type II and one matched control. Cell clustering, annotation, and identification of differentially expressed genes (DEGs) were conducted using standard Seurat workflow. We focused on the molecular alterations in three major glial cell types: astrocytes, microglia, and oligodendrocytes. To functionally interpret the DEGs, we performed enrichment analyses using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Results: Our profiling revealed a profoundly reconstituted cellular ecosystem in the FCD cortex. We found a marked expansion of microglia (65.57% vs. 47.02%; a ~39% relative increase) and astrocytes (10.98% vs. 4.11%; a ~167% relative increase), alongside a severe depletion of oligodendrocytes (8.12% vs. 30.63%; a ~73% relative decrease). Critically, a core set of 128 differentially expressed genes (DEGs) was shared across these glial populations, featuring consistent upregulation of RAC1 and downregulation of ATP5F1D, pointing to convergent pro-inflammatory and mitochondrial dysfunction pathways. Enrichment analyses further demonstrated a coordinated engagement of neuroinflammatory pathways, most notably IL-17 signaling. Subsequent cell–cell communication inference revealed a broad attenuation of intercellular signaling, with a 35% reduction in interaction numbers, indicating a breakdown of coordinated cellular crosstalk. Conclusions: This exploratory single-cell study provides preliminary evidence of a convergent glial pathology in FCD, characterized by shared molecular disruptions in inflammation and metabolism. Our findings highlight RAC1 and IL-17 signaling as potentially actionable pathways, warranting further investigation into their therapeutic potential for mitigating epileptogenesis in FCD. Full article

Diet influences brain health through many connected metabolic and molecular pathways, and these effects are stronger in obesity. This review links diet quality with cognitive decline and dementia risk. Ultra-processed, high-fat, high-sugar diets drive weight gain, insulin resistance, and chronic inflammation. These changes trigger brain oxidative stress, reduce DNA repair, deplete NAD⁺, disturb sirtuin/PARP balance, and alter epigenetic marks. Gut dysbiosis and leaky gut add inflammatory signals, weaken the blood–brain barrier, and disrupt microglia. Mediterranean and MIND diets, rich in plants, fiber, polyphenols, and omega-3 fats, slow cognitive decline and lower dementia risk. Trials show extra benefit when diet improves alongside exercise and vascular risk control. Specific nutrients can help in certain settings. DHA and EPA support brain health in people with low omega-3 status or early disease. B-vitamins slow brain shrinkage in mild cognitive impairment when homocysteine is high. Vitamin D correction is beneficial when levels are low. A practical plan emphasizes healthy eating and good metabolic control. It includes screening for deficiencies and supporting the microbiome with fiber and fermented foods. Mechanism-based add-ons, such as NAD⁺ boosters, deserve testing in lifestyle-focused trials. Together, these measures may reduce diet-related brain risk across the life span. At the same time, artificial intelligence can integrate diet exposures, adiposity, metabolic markers, multi-omics, neuroimaging, and digital phenotyping. This can identify high-risk phenotypes, refine causal links along the diet–obesity–brain axis, and personalize nutrition-plus-lifestyle interventions. It can also highlight safety, equity, and privacy considerations. Translationally, a pattern-first strategy can support early screening and personalized risk reduction by integrating diet quality, adiposity, vascular risk, micronutrient status, and microbiome-responsive behaviors. AI can aid measurement and risk stratification when developed with privacy, equity, and interpretability safeguards, but clinical decisions should remain mechanism-aligned and trial-anchored. Full article

Background/Objectives: Microglia are the primary immune cells in the central nervous system (CNS) and are known as “resident” macrophages. The aim of this study was to determine the effect of acute ethanol (EtOH) on the microglia state and monocyte infiltration into the CNS, with particular attention to the role of peripheral and central dopamine (DA) D2 receptors (D2Rs) in mediating EtOH effects on peripheral and central substrates. We hypothesize that EtOH interacts with peripheral immune mediators via D2Rs including monocyte-derived macrophages (MDMs) to modulate midbrain neurons, DA transmission in the mesolimbic pathway from the ventral tegmental area (VTA) to nucleus accumbens (NAc), and the intoxicating effects of acute EtOH. Methods: Using the Macrophage FAS-Induced Apoptosis (MaFIA) mouse model (GFP+ on Csf1r promoter), we assessed the effects of three intraperitoneal (IP) doses of EtOH (1, 2, and 4 g/kg) at three time points (0.5, 1, and 2 h after injection) on D2R expression in blood leukocytes and microglia, as well as midbrain neuronal activity, DA release, and behavior. Results: Acute EtOH significantly enhanced lymphocyte and monocyte D2R expression at 1.0 g/kg by 2 h after injection in vivo but decreased D2R expression in vitro. Ethanol enhanced microglia D2R expression in the NAc, while not altering D2R expression in the VTA, but altered the microglia state in these areas, shifting them toward an inflammatory phenotype. Acute EtOH induced prolonged and progressive hypersensitivity of D2R activation of VTA GABA neurons. Intravenous injection of the macrophage depleter liposomal clodronate significantly reduced blood macrophages by 55.3% and blocked the typical inhibition of VTA GABA neurons by EtOH, as well as the enhancement of DA levels in the NAc, and the locomotor indices of intoxication produced by acute EtOH, but not choice place preference. Conclusions: These findings strongly suggest a neuroimmune peripheral connection for acute low-dose EtOH use and challenge the dogma that central actions of EtOH exclusively mediate its effect on DA neuronal activity and release. Full article

Parkinson’s disease is the second most common neurodegenerative movement disorder caused by the death of dopaminergic neurons in the Substantia nigra. The motor symptoms of Parkinson’s disease only become apparent in the late stages, whereas non-motor impairments often manifest earlier. Therefore, devising adequate experimental models to study the pathogenesis of Parkinson’s disease is of fundamental scientific importance. In this study, we aimed to evaluate the behavioral and neurochemical characteristics in a model of the premotor stage of parkinsonism in mice induced by chronic administration of a low dose of methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP. Administering 3 mg/kg of the toxin for 35 days does not cause motor deficits, except in fine motor skills, and results in impaired spatial learning. In addition, this stage is characterized by the depletion of striatum and prefrontal cortex dopamine, decreased tyrosine hydroxylase in striatum and Substantia nigra, increased cytochrome oxidase and superoxide dismutase expression, and microglia activation. Concluding, the presented model made it possible to identify a complex of physiological and neurochemical disorders characteristic of the early stage of Parkinsonism. Full article

Murine microglia exhibit rapid self-renewal upon removal from the postnatal brain. However, the signaling pathways that regulate microglial repopulation remain largely unclear. To address this knowledge gap, we depleted microglia from mixed glial cultures using anti-CD11b magnetic particles and cultured them for 4 weeks to monitor their repopulation ability in vitro. Flow cytometry and immunocytochemistry revealed that anti-CD11b bead treatment effectively eliminated >95% of microglia in mixed glial cultures. Following removal, the number of CX3CR1-positive microglia gradually increased; when a specific threshold was reached, repopulation ceased without any discernable rise in cell death. Cell cycle and 5-ethynyl-2′-deoxyuridine incorporation assays suggested the active proliferation of repopulating microglia at d7. Time-lapse imaging demonstrated post-removal division of microglia. Colony-stimulating factor 1 receptor-phosphoinositide 3-kinase-protein kinase B signaling was identified as crucial for microglial repopulation, as pharmacological inhibition or neutralization of the pathway significantly abrogated repopulation. Transwell cocultures revealed that resident microglia competitively inhibited microglial proliferation probably through contact inhibition. This in vitro microglial removal system provides valuable insights into the mechanisms underlying microglial proliferation. Full article

High-altitude cognitive impairment (HACI) results from acute or chronic exposure to hypoxic conditions. Brain lipid homeostasis is crucial for cognitive function, and lipid droplet (LD) accumulation in glia cells is linked to cognitive decline in aging and stroke. However, whether high-altitude exposure affects brain lipid homeostasis is unclear. Microglia, key regulators of brain homeostasis and inflammation, play a significant role in pathological cognitive impairment and are implicated in LD formation. This study investigates whether lipid dysregulation contributes to HACI and explores microglia-driven mechanisms and potential interventions. Mice were exposed to a simulated 7000 m altitude for 48 h, followed by a week of recovery. Cognitive function and LD accumulation in brain cells were assessed. Microglia were depleted using PLX5622, and mice were exposed to hypoxia or lipopolysaccharide (LPS) to validate microglia’s role in driving astrocytic LD accumulation and cognitive decline. Minocycline was used to inhibit inflammation. In vitro, co-culture systems of microglia and astrocytes were employed to confirm microglia-derived pro-inflammatory factors’ role in astrocytic LD accumulation. Hypobaric hypoxia exposure induced persistent cognitive impairment and LD accumulation in hippocampal astrocytes and microglia. Microglia depletion alleviated cognitive deficits and reduced astrocytic LD accumulation. Hypoxia or LPS did not directly cause LD accumulation in astrocytes but activated microglia to release IL-1β, inducing astrocytic LD accumulation. Microglia depletion also mitigated LPS-induced cognitive impairment and astrocytic LD accumulation. Minocycline reduced hypoxia-induced LD accumulation in co-cultured astrocytes and improved cognitive function. Hypoxia triggers pro-inflammatory microglial activation, leading to LD accumulation and the release of IL-1β, which drives astrocytic LD accumulation and neuroinflammation, exacerbating HACI. Minocycline effectively restores brain lipid homeostasis and mitigates cognitive impairment. This study provides novel insights into HACI mechanisms and suggests potential therapeutic strategies. Full article

Background: An acute angle-closure attack (AAC) is an ocular emergency that results from a rapid increase in intraocular pressure (IOP). Sustained IOP elevation induces severe degeneration of retinal ganglion cells (RGCs) without treatment. Overactivated microglia, key participants in innate immune responses, have critical roles in the pathogenesis of IOP-induced RGC death, although precise mechanisms remain unclear. In the present study, we used a rat ex vivo acute glaucoma model to investigate the role of microglial signaling in RGC death and examined whether pharmacological depletion of microglia using a CSF-1R inhibitor, PLX5622, exerts neuroprotection against pressure-induced retinal injury. Methods: Ex vivo rat retinas were exposed to hydrostatic pressure (10 mmHg or 75 mmHg) for 24 h. Pressure-dependent changes in retinal microglia and RGCs were detected by immunofluorescence. Morphological changes in the retina and RGC apoptosis were examined using light microscopy and TUNEL staining, respectively. The expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β were examined using Western blotting. Effects of PLX5622, an agent that depletes microglia, were examined in morphology, apoptosis, and protein expression assays, while TAK-242, a TLR4 inhibitor, was examined against protein expression. Results: Pressure loading at 75 mmHg markedly increased activated microglia and apoptotic RGCs in the isolated retinas. Western blotting revealed increases in expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β at 75 mmHg compared to 10 mmHg. Inhibition of pressure-induced increases in NLRP3 by TAK-242 indicates that pressure elevation induces RGC death via activation of the TLR4–NLRP3 inflammasome cascade. PLX5622 depleted microglia at 75 mmHg and significantly decreased expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β at 75 mmHg, resulting in preservation of RGCs. Conclusions: These results indicate that pressure elevation induces proliferation of inflammatory microglia and promotes IL-1β production via activation of the TLR4–NLRP3 inflammasome cascade, resulting in RGC death. Pharmacological depletion of microglia with PLX5622 could be a potential neuroprotective approach to preserve RGCs from inflammatory cytokines in AAC eyes. Full article

Glutamate is an excitatory neurotransmitter in the central nervous system (CNS) that mediates synaptic transmission. However, glutamate homeostasis among neural cells is broken in cerebral ischemia. Excessive glutamate triggers N-methyl-d-aspartate receptors (NMDARs) in postsynaptic neurons, leading to intracellular calcium (Ca²⁺) overload and excitoneurotoxicity. At this moment, L-lactate may affect NMDARs and play a protective role in cerebral ischemia. This work proposes that L-lactate regulates glutamate signaling among neural cells. But, dysregulation of L-lactate in glutamate signaling cascades contributes to glutamate excitotoxicity in cerebral ischemia. In detail, L-lactate regulates the glutamine(Gln)-glutamate cycle between astrocytes and presynaptic neurons, which triggers the astroglial L-lactate-sensitive receptor (LLR)-cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, coordinating astroglial glutamate uptake and neuronal glutamate transmission. L-lactate mediates glutamate signaling and synaptic transmission among neural cells. In addition, L-lactate promotes the function of mitochondrial calcium uniporter complex (MCUC), which quickly depletes intracellular Ca²⁺ in postsynaptic neurons. In addition, L-lactate can promote the conversion of microglia from the pro-inflammatory (M1) to anti-inflammatory (M2) phenotype. Therefore, regulation of L-lactate in glutamate signaling in the CNS might become a preventive target for cerebral ischemia. Full article

NAD⁺ is a fundamental molecule participating as a redox cofactor in several metabolic reactions and has a neuroprotective role associated with oxidate stress. Despite its critical role, NAD⁺ levels sharply decline with age, contributing to the pathogenesis of aging-related diseases. Supplementation with nicotinamide riboside (NR), also known as a form of vitamin B3, a biochemical precursor of NAD⁺, may replenish this depletion. Background/Objectives: Mounting evidence suggests that dietary supplementation with NR, a form of vitamin B3 and a biochemical precursor of NAD⁺, enhances NAD⁺ bioavailability and prevents the detrimental effects on sleep, cognitive function, mitochondrial function, and insulin sensitivity. However, there is a paucity of studies focused on how NR administration affects sleep patterns. This narrative review summarizes the current state of scientific knowledge on the effects of nicotinamide riboside supplementation on sleep. Results: Pre-clinical studies indicate that NR enhances the performance of the clock genes BMAL1 and PER2, and ameliorates chronic sleep deprivation-induced cognitive impairment, potentially by alleviating oxidative stress and mitochondrial impairment in microglia. NR supplementation also increased REM sleep and reduced NREM sleep by approximately 17%. In human studies, NR improved sleep efficiency in young and middle-aged male individuals with insomnia. It also improved sleep quality and reduced fatigue and drowsiness in older adults. More research is warranted to understand the impacts of NR on sleep for women. Conclusions: NR supplementation is a reliable and effective alternative to boost NAD⁺ levels and may ameliorate sleep patterns. Full article