A New Perspective on Mechanisms of Neurodegeneration in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis: the Early and Critical Role of Platelets in Neuro/Axonal Loss

Journal of Neuroimmune Pharmacology, Journal Year: 2025, Volume and Issue: 20(1)

Published: Feb. 4, 2025

Abstract Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disorder, with limited treatment options. This disease characterized by differential pathophysiology between grey matter (GM) and white (WM). The predominant WM hallmark the perivascular plaque, associated blood brain barrier (BBB) loss of function, lymphocytic infiltration, microglial reactivity, demyelination axonal injury adequately addressed immunomodulatory drugs. By contrast, mechanisms underlying GM damage remain obscure, consequences for neuroprotective strategies. Cortical pathology already significant in early MS reduced BBB disruption infiltration relative to WM, but highly inflammatory environment, neuro/axonal loss. There no satisfactory explanation occurrence neurodegeneration without large-scale cell influx cortical GM. A candidate mechanism suggests that it results from soluble factors originating meningeal aggregates, which diffuse into tissue trigger activation. However, recent literature highlights role platelets inflammation, together relationship coagulation factors, particularly fibrinogen, MS. Using experimental encephalomyelitis (EAE) model, we identified as drivers neuroinflammation platelet-neuron associations pre-symptomatic stage. We propose fibrinogen leakage across signal platelet represent major participant neurodegeneration. concept compatible new appreciation immune cells neuronal driven sequestered meninges. Graphical

Language: Английский

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cGAS-STING targeting offers novel therapeutic opportunities in neurological diseases

Ageing Research Reviews, Journal Year: 2025, Volume and Issue: 105, P. 102691 - 102691

Published: Feb. 13, 2025

Language: Английский

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Cell type mapping reveals tissue niches and interactions in subcortical multiple sclerosis lesions

Nature Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 5, 2024

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Inflammation gradually compartmentalized and restricted to specific tissue niches such as lesion rim. However, precise cell type composition niches, their interactions changes between active inactive stages are incompletely understood. We used single-nucleus spatial transcriptomics from subcortical MS corresponding control tissues map types associated pathways nonlesion areas. identified perivascular spaces, inflamed rim or core that with glial scar cilia-forming astrocyte subtype. Focusing on lesions, we uncovered cell–cell communication events myeloid, endothelial types. Our results provide insight into cellular composition, multicellular programs intercellular in along conversion homeostatic dysfunctional state underlying progression MS. Lerma-Martin et al. generated paired RNA sequencing dataset multiple identifying key driving inflammation at

Language: Английский

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The contribution of tumor necrosis factor to multiple sclerosis: a possible role in progression independent of relapse?

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Aug. 21, 2024

Tumor necrosis factor (TNF) is a pleiotropic cytokine regulating many physiological and pathological immune-mediated processes. Specifically, it has been recognized as an essential pro-inflammatory implicated in multiple sclerosis (MS) pathogenesis progression. MS chronic disease of the central nervous system, characterized by multifocal acute inflammatory demyelination white grey matter, along with neuroaxonal loss. A recent concept field research disability resulting from Progression Independent Relapse Activity (PIRA). PIRA recognizes that accumulation since early phase can occur independently relapse activity overcoming traditional dualistic view either relapsing-inflammatory or progressive-neurodegenerative disease. Several studies have demonstrated upregulation TNF expression both active brain lesions. Additionally, elevated levels observed serum cerebrospinal fluid patients. appears to play significant role maintaining intrathecal inflammation, promoting axonal damage neurodegeneration, consequently contributing progression accumulation. In summary, this review highlights current understanding its receptors progression, specifically focusing on relatively unexplored condition. Further area holds promise for potential therapeutic interventions targeting mitigate

Language: Английский

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Comparative targeted lipidomics between serum and cerebrospinal fluid of multiple sclerosis patients shows sex and age-specific differences of endocannabinoids and glucocorticoids

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: Oct. 10, 2024

Multiple sclerosis (MS) is a complex chronic neuroinflammatory disease characterized by demyelination leading to neuronal dysfunction and neurodegeneration manifested various neurological impairments. The endocannabinoid system (ECS) lipid signalling network, which plays multiple roles in the central nervous periphery, including synaptic signal transmission modulation of inflammation. ECS has been identified as potential target for development novel therapeutic interventions MS patients. It remains unclear whether ECS-associated metabolites are changed could serve biomarkers blood or cerebrospinal fluid (CSF). In this retrospective study we applied targeted lipidomics matching CSF serum samples 74 80 non-neuroinflammatory control We found that MS-associated lipidomic changes overall did not coincide between serum. While glucocorticoids correlated positively, only (eCB) 2-arachidonoyl glycerol (2-AG) showed weak positive correlation (r = 0.3, p < 0.05) Peptide endocannabinoids be quantified first time but differ controls. patients elevated levels prostaglandin E2 steaorylethanolamide serum, 2-oleoylglycerol cortisol CSF. Sex-specific differences were showing increased 2-AG males only. Overall, arachidonic acid was males. Interestingly, eCBs positively with age due young relapsing-remitting Our findings reveal significant discrepancies underscoring measuring matrices optimal detecting system. sex age-specific analytes stress axis specifically supports role may relevant drug strategies.

Language: Английский

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Spatial Transcriptomics: Biotechnologies, Computational Tools, and Neuroscience Applications

Small Methods, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 6, 2025

Spatial transcriptomics (ST) represents a revolutionary approach in molecular biology, providing unprecedented insights into the spatial organization of gene expression within tissues. This review aims to elucidate advancements ST technologies, their computational tools, and pivotal applications neuroscience. It is begun with historical overview, tracing evolution from early image-based techniques contemporary sequence-based methods. Subsequently, methods essential for data analysis, including preprocessing, cell type annotation, clustering, detection spatially variable genes, cell-cell interaction 3D multi-slices integration are discussed. The central focus this application neuroscience, where it has significantly contributed understanding brain's complexity. Through ST, researchers advance brain atlas projects, gain development, explore neuroimmune dysfunctions, particularly tumors. Additionally, enhances neuronal vulnerability neurodegenerative diseases like Alzheimer's neuropsychiatric disorders such as schizophrenia. In conclusion, while already profoundly impacted challenges remain issues enhancing sequencing technologies developing robust tools. underscores transformative potential paving way new therapeutic research.

Language: Английский

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The Crucial Role of the Blood–Brain Barrier in Neurodegenerative Diseases: Mechanisms of Disruption and Therapeutic Implications

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(2), P. 386 - 386

Published: Jan. 9, 2025

The blood-brain barrier (BBB) is a crucial structure that maintains brain homeostasis by regulating the entry of molecules and cells from bloodstream into central nervous system (CNS). Neurodegenerative diseases such as Alzheimer's Parkinson's disease, well ischemic stroke, compromise integrity BBB. This leads to increased permeability infiltration harmful substances, thereby accelerating neurodegeneration. In this review, we explore mechanisms underlying BBB disruption, including oxidative stress, neuroinflammation, vascular dysfunction, loss tight junction integrity, in patients with neurodegenerative diseases. We discuss how breakdown contributes neurotoxicity, abnormal accumulation pathological proteins, all which exacerbate neuronal damage facilitate disease progression. Furthermore, potential therapeutic strategies aimed at preserving or restoring function, anti-inflammatory treatments, antioxidant therapies, approaches enhance integrity. Given role neurodegeneration, maintaining its represents promising approach slow prevent progression

Language: Английский

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Multi-disciplinary research will be the key to stop, restore, and end MS

Multiple Sclerosis Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

The past 25 years have brought extraordinary advances in our understanding of MS pathogenesis and the subsequent development effective therapies. Collaborative genetics efforts uncovered association 236 common DNA variants with disease susceptibility first severity, paving way to more therapies, particularly for progressive forms disease. In parallel, addition established environmental triggers or modifiers, new collaborative work has revealed associations components gut microbiome. This research opened a exciting prospect exploring gut-brain axis, potential also provide pharmacologic targets diet-based Finally, availability massive amounts information unprecedented computer power, wave artificial intelligence (AI)-based is sprawling. These investigations will result statistically powerful predictive models identify individuals at risk even before clinically apparent. Furthermore, using approaches like semantic representation causal inference, some these be explainable biomedical terms, thus making them trusted facilitating their implementation clinical setting. thread that characterizes all multi-disciplinary collaboration among scientists form formal consortia, working groups, ad hoc partnerships. may "secret sauce" modern science best strategy stop, restore, end MS.

Language: Английский

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Early Synapse-Specific Alterations of Photoreceptor Mitochondria in the EAE Mouse Model of Multiple Sclerosis

Cells, Journal Year: 2025, Volume and Issue: 14(3), P. 206 - 206

Published: Jan. 30, 2025

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) linked to many neurological disabilities. The visual frequently impaired in MS. In previous studies, we observed early malfunctions rod photoreceptor ribbon synapses EAE mouse model MS that included alterations synaptic vesicle cycling and disturbances presynaptic Ca2+ homeostasis. Since these events are highly energy-demanding, analyzed whether mitochondria, which play a major role energy metabolism, might be involved at stage. Rod terminals contain single large mitochondrion next ribbon. present study, expression functionally relevant mitochondrial proteins (MIC60, ATP5B, COX1, PINK1, DRP1) by high-resolution qualitative quantitative immunofluorescence microscopy, immunogold electron microscopy Western blot experiments. We decreased mitochondria photoreceptors stage, suggesting dysfunctions important synapse pathology. Interestingly, were strongly compromised EAE, whereas extra-synaptic inner segments remained unchanged, demonstrating functional heterogeneity mitochondria.

Language: Английский

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A Quarter Century of Calcium-Permeable Ion Channel, TRPV4: Perspectives on Expression and Function in Endothelial Cells - Time to Translate

Published: Jan. 1, 2025

Language: Английский

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