Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review)

International Journal of Molecular Medicine, Journal Year: 2024, Volume and Issue: 53(5)

Published: April 2, 2024

Chronic neuroinflammation serves a key role in the onset and progression of neurodegenerative disorders. Mitochondria serve as central regulators neuroinflammation. In addition to providing energy cells, mitochondria also participate immunoinflammatory response disorders including Alzheimer's disease, Parkinson's multiple sclerosis epilepsy, by regulating processes such cell death inflammasome activation. Under inflammatory conditions, mitochondrial oxidative stress, epigenetics, dynamics calcium homeostasis imbalance may underlying regulatory mechanisms for these diseases. Therefore, investigating related dysfunction result therapeutic strategies against chronic neurodegeneration. The present review summarizes neuroinflammatory diseases current treatment approaches that target

Language: Английский

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Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis

New England Journal of Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: April 8, 2025

Throughout the course of multiple sclerosis, gradually progressive neurologic impairment can occur, which has been called disability accrual. Current disease-modifying therapies for sclerosis have limited effects on accrual unrelated to relapses, is thought be partially caused by chronic, nonresolving neuroinflammation within central nervous system. Tolebrutinib an oral, brain-penetrant Bruton's tyrosine kinase inhibitor that targets myeloid cells (including microglia) and B in both periphery There are no approved treatments nonrelapsing secondary sclerosis. In a phase 3, double-blind, placebo-controlled, event-driven trial, we randomly assigned participants with 2:1 ratio, receive tolebrutinib (60 mg once daily) or matching placebo. The primary end point was confirmed progression sustained at least 6 months, assessed time-to-event analysis. A total 1131 underwent randomization: 754 were 377 median follow-up 133 weeks. smaller percentage group than placebo had months (22.6% vs. 30.7%; hazard 0.69; 95% confidence interval, 0.55 0.88; P = 0.003). Serious adverse events occurred 15.0% 10.4% those group. 4.0% 1.6% increases alanine aminotransferase levels more 3 times upper limit normal range. risk lower among who received treatment (Funded Sanofi; HERCULES ClinicalTrials.gov number, NCT04411641.).

Language: Английский

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Disentangling the heterogeneity of multiple sclerosis through identification of independent neuropathological dimensions

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 147(1)

Published: May 21, 2024

Abstract Multiple sclerosis (MS) is a heterogeneous neurological disorder with regards to clinical presentation and pathophysiology. Here, we investigated the heterogeneity of MS by performing an exploratory factor analysis on quantitative qualitative neuropathology data collected for 226 donors in Netherlands Brain Bank autopsy cohort. Three promising dimensions were identified subsequently validated clinical, neuropathological, genetic data. Dimension 1 ranged from predominance remyelinated inactive lesions extensive pathological changes, higher proportions active mixed lesions, foamy microglia morphology. This pattern was positively correlated more severe disease, presence B T cells, neuroaxonal damage. Scoring high dimension 2 associated reactive sites, nodules. These had less specific cortical risk variants human leukocyte antigen region, latter indicating connection between disease onset this neuropathological dimension. Donors scoring 3 showed increased lesional pathology relatively ramified longer duration, subpial involvement adaptive immune system, axonal Taken together, three may represent (1) demyelination cell activity progression, (2) (re)activity possibly lesion initiation, (3) loss scar formation. Our findings highlight that thorough understanding interplay multiple characteristics crucial understand pathology, as well its association predictors outcomes. The scores can serve important starting point further disentanglement translation into observations interventions living cohorts MS.

Language: Английский

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Toward identifying key mechanisms of progression in multiple sclerosis

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 47(1), P. 58 - 70

Published: Dec. 14, 2023

Language: Английский

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Traumatic brain injury alters the effects of class II invariant peptide (CLIP) antagonism on chronic meningeal CLIP + B cells, neuropathology, and neurobehavioral impairment in 5xFAD mice

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

Published: June 27, 2024

Abstract Background Traumatic brain injury (TBI) is a significant risk factor for Alzheimer’s disease (AD), and accumulating evidence supports role adaptive immune B T cells in both TBI AD pathogenesis. We previously identified cell major histocompatibility complex class II (MHCII)-associated invariant chain peptide (CLIP)-positive expansion after TBI. also showed that antagonizing CLIP binding to the antigen presenting groove of MHCII acutely reduced + splenic was neuroprotective. The current study investigated chronic effects 5xFAD mouse model, with without Methods 12-week-old male wild type (WT) mice were administered either antagonist (CAP) or vehicle, once at 30 min sham lateral fluid percussion (FPI). Analyses included flow cytometric analysis dural meninges spleen, histopathological brain, magnetic resonance diffusion tensor imaging, cerebrovascular analysis, assessment motor neurobehavioral function over ensuing 6 months. Results 9-month-old had significantly more compared age-matched WT mice. A one-time treatment CAP this population Importantly, improved some immune, histopathological, impairments six Although FPI did not further elevate meningeal cells, it negate ability reduce 3 months age exacerbated aspects pathology mice, including reducing hippocampal neurogenesis, increasing plaque deposition CA3, altering microgliosis, disrupting structure. ameliorated but all these effects.

Language: Английский

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Bruton’s tyrosine kinase-bearing B cells and microglia in neuromyelitis optica spectrum disorder

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Dec. 21, 2023

Abstract Background Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well astrocyte–microglia interaction, which both contribute to evolution NMOSD lesions. Main body Through transcriptomic and flow cytometry analyses, we found Bruton’s tyrosine kinase (BTK), a crucial protein was upregulated in blood cerebrospinal fluid patients. Blockade BTK with zanubrutinib, highly specific inhibitor, mitigated activation maturation B cells reduced production causal aquaporin-4 (AQP4) autoantibodies. In mouse model NMO, pBTK expression were significantly increased microglia. Transmission electron microscope scan demonstrated inhibitor ameliorated demyelination, edema, axonal injury NMO mice. same mice colocalization GFAP Iba-1 immunofluorescence indicated noticeable increase astrocytes–microglia alleviated by zanubrutinib. The smart-seq analysis treatment instigated microglial transcriptome changes including downregulation chemokine-related genes involved top 5 biological processes related cell adhesion migration, are likely responsible for crosstalk microglia astrocytes. Conclusions Our results show activity enhanced inhibition contributes amelioration pathology. These data collectively reveal mechanism action corroborate viable therapeutic target.

Language: Английский

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Bruton tyrosine kinase inhibitors in multiple sclerosis: evidence and expectations

Current Opinion in Neurology, Journal Year: 2024, Volume and Issue: 37(3), P. 237 - 244

Published: March 27, 2024

Despite availability of high-efficacy therapies for multiple sclerosis (MS), many patients experience significant disability worsening due to limited effects currently available drugs on central nervous system (CNS)-compartmentalized inflammation. Bruton tyrosine kinase (BTK) is an intracellular signaling molecule involved in regulation maturation, survival, migration, and activation B cells microglia, which are players the immunopathogenesis progressive MS. Therefore, CNS-penetrant BTK inhibitors may better prevent disease progression by targeting immune both sides blood-brain barrier. This review gives overview preliminary results clinical trials.

Language: Английский

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Heterogeneity of mature oligodendrocytes in the central nervous system

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(5), P. 1336 - 1349

Published: June 26, 2024

Mature oligodendrocytes form myelin sheaths that are crucial for the insulation of axons and efficient signal transmission in central nervous system. Recent evidence has challenged classical view functionally static mature oligodendrocyte revealed a gamut dynamic functions such as ability to modulate neuronal circuitry provide metabolic support axons. Despite recognition potential heterogeneity function, comprehensive summary diversity is lacking. We delve into early 20 th -century studies by Robertson Río-Hortega laid foundation modern identification regional morphological oligodendrocytes. Indeed, recent morphologic functional call question long-assumed homogeneity function through distinct subtypes with varying myelination preferences. Furthermore, molecular investigations, employing techniques single cell/nucleus RNA sequencing, consistently unveil at least six subpopulations human system highly transcriptomically diverse vary region. Age disease related variation denotes impact pathological conditions multiple sclerosis, Alzheimer’s disease, psychiatric disorders. Nevertheless, caution warranted when subclassifying because simplification needed make conclusions about cell identity from temporally confined investigations. Future leveraging advanced like spatial transcriptomics single-cell proteomics promise more nuanced understanding heterogeneity. Such research avenues precisely evaluate care understand mitigating influence species, sex, region, age, hold development therapeutic interventions targeting varied pathology.

Language: Английский

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Baseline serum neurofilament light chain levels differentiate aggressive from benign forms of relapsing–remitting multiple sclerosis: a 20-year follow-up cohort

Journal of Neurology, Journal Year: 2023, Volume and Issue: 271(4), P. 1599 - 1609

Published: Dec. 12, 2023

Abstract Background and objectives Serum biomarkers are emerging as useful prognostic tools for multiple sclerosis (MS); however, long-term studies lacking. We aimed to evaluate the value of serum levels neurofilament light chain (NfL), total tau, glial fibrillary acidic protein (GFAP), chitinase 3-like-1 (CHI3L1) measured close time MS onset. Methods In this retrospective, exploratory, observational, case controls study, patients with relapsing–remitting (RRMS) available baseline samples prospectively follow-up in our unit a long were selected based on their clinical evolution form two groups: (1) benign RRMS (bRRMS) group, defined an Expanded Disability Status Scale (EDSS) score ≤ 3 at ≥ 10 years follow-up; (2) aggressive (aRRMS) EDSS 6 15 follow-up. An age-matched healthy control (HC) group was selected. NfL, GFAP quantified using single-molecule array (SIMOA), CHI3L1 ELISA. Results Thirty-one bRRMS, 19 aRRMS, HC included. The median from sample collection 17.74 (interquartile range, 14.60–20.37). Bivariate multivariate analyses revealed significantly higher NfL aRRMS than bRRMS group. A receiver operating characteristic curve analysis identified level most efficient marker distinguishing bRRMS. Discussion This proof-of-concept study comparing groups reinforces potential role promising disability marker. contrast, GFAP, demonstrated lower or no ability differentiate between outcomes RRMS.

Language: Английский

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Potential mechanisms of how B-cell depletion works in MOGAD

Multiple Sclerosis and Related Disorders, Journal Year: 2025, Volume and Issue: 93, P. 106269 - 106269

Published: Jan. 1, 2025

Language: Английский

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