NLRX1 limits inflammatory neurodegeneration in the anterior visual pathway

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Jan. 28, 2025

Chronic innate immune activation in the central nervous system (CNS) significantly contributes to neurodegeneration progressive multiple sclerosis (MS). Using experimental autoimmune encephalomyelitis (EAE) models, we discovered that NLRX1 protects neurons anterior visual pathway from inflammatory neurodegeneration. We quantified retinal ganglion cell (RGC) density and optic nerve axonal degeneration, gliosis, T-cell infiltration Nlrx1−/− wild-type (WT) EAE mice found increased RGC loss injury compared WT both active immunization spontaneous opticospinal (OSE) models. To minimize effects of on peripheral lymphocyte priming during EAE, performed adoptive transfer experiments, which activated myelin-specific T cells were transferred into lymphocyte-deficient Rag−/− or Nlrx1−/−Rag−/− mice. In this model, more severe microgliosis astrogliosis mice, suggesting a regulatory role cells. Transcriptome analysis primary astrocytes with LPS IFNγ demonstrated suppresses NF-κB regulates mitochondrial oxidative phosphorylation reactive astrocytes. The novel pharmacologic activators NX-13 LABP-66 decreased LPS-mediated gene expression cytokines chemokines mixed glial cultures. Moreover, treating oral LABP-66, vehicle, after onset paralysis resulted less These data suggest have potential limit This study highlights could serve as promising target for neuroprotection MS other neurodegenerative diseases. Further studies are needed better understand cell-specific mechanisms underlying neuroprotective response inflammation CNS.

Language: Английский

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Proteolysis‐Based Biomarker Repertoire of the Neurofilament Proteome

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(3)

Published: March 1, 2025

ABSTRACT Neurodegeneration presents a significant challenge in ageing populations, often being detected too late for effective intervention. Biomarkers have shown great potential addressing this issue, with neurofilament (Nf) proteins emerging as validated biomarkers presently transitioning from research to routine laboratory use. Whilst advances large‐scale quantitative analyses enabled the targeted study of proteolytic Nf fragments blood, complete landscape breakdown remains unknown. This comprehensive atlas human isoform ( Z ) degradome, based on number known cleavage sites x ). The full scale degradome is described by formula: = (( + 1) × 2)/2) − 1. resulting (NDA) was through triple‐layer approach using vitro data (open access at: https://doi.org/10.5522/04/25689378.v1 NDA offers valuable applications biomarker detection, antibody development, exploration autoimmunity and understanding aggregate formation. Analysis reveals novel insights into neurodegenerative diseases investigating peptide pools affected genetic mutations genome alterations pathways. annotated publicly available database resource, supporting advancements affinity‐based tests informed selection minimising biases label‐free approaches. In conclusion, highlights biological significance dynamic pool coexisting peptides, providing framework that can be applied other proteins. image

Language: Английский

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Advances in neurofilament light chain analysis

Advances in clinical chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Proteomics and relationship with axonal pathology in multiple sclerosis: 5-year diffusion tensor imaging study

Brain Communications, Journal Year: 2023, Volume and Issue: 5(3)

Published: Jan. 1, 2023

Abstract Blood-based biomarkers can be economic and easily accessible tools for monitoring predicting disease activity in multiple sclerosis. The objective of this study was to determine the predictive value a multivariate proteomic assay concurrent future microstructural/axonal brain pathology longitudinal heterogeneous group people with A analysis obtained on serum samples from 202 sclerosis (148 relapsing-remitting 54 progressive) at baseline 5-year follow-up. concentration 21 proteins related pathways pathophysiology derived using Proximity Extension Assay Olink platform. Patients were imaged same 3T MRI scanner both timepoints. Тhe rate whole brain, white matter grey atrophy over follow-up determined multi-timepoint Structural Image Evaluation, Normalisation, Atrophy algorithms. Lesion burden measures also assessed. severity microstructural axonal quantified diffusion tensor imaging. Fractional anisotropy mean diffusivity normal-appearing tissue, matter, T2 T1 lesions calculated. Age, sex body mass index-adjusted step-wise regression models used. Glial fibrillary acidic protein most common highest-ranked biomarker associated greater central nervous system alterations (P < 0.001). levels glial protein, protogenin precursor, neurofilament light chain myelin oligodendrocyte 0.009), whereas higher chain, osteopontin lower precursor 0.016). Higher level significant predictor CNS as measured by tissue fractional (standardized β = −0.397/0.327, P 0.001), −0.466, 0.0012), 0.346, 0.011) lesion 0.416, 0.001) Serum myelin-oligodendrocyte glycoprotein, contactin-2 additionally independently worse concomitant pathology. disability progression (Exp(B) 8.65, 0.004). Multiple are imaging Baseline predict progression.

Language: Английский

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The GFAP proteoform puzzle: How to advance GFAP as a fluid biomarker in neurological diseases

Journal of Neurochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 17, 2024

Abstract Glial fibrillary acidic protein (GFAP) is a well‐established biomarker of reactive astrogliosis in the central nervous system because its elevated levels following brain injury and various neurological disorders. The advent ultra‐sensitive methods for measuring low‐abundant proteins has significantly enhanced our understanding GFAP serum or plasma patients with diverse diseases. Clinical studies have demonstrated that holds promise both as diagnostic prognostic biomarker, including but not limited to individuals Alzheimer's disease. exhibits forms structures, herein referred proteoform complexity, encompassing conformational dynamics, isoforms post‐translational modifications (PTMs). In this review, we explore how complexity influences detection, which may affect differential performance different biological fluids can provide valuable insights into underlying processes. Additionally, proteoforms are often disease‐specific, review provides suggestions highlights areas focus on development new assays GFAP, isoforms, PTMs, discharge mechanisms, breakdown products, higher‐order species interacting partners. By addressing knowledge gaps highlighted aim support clinical translation interpretation CSF blood reliable, reproducible specific tests. To enhance disease pathology comprehension optimise thorough detected biofluids essential. image

Language: Английский

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NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study

Journal of Neurology Neurosurgery & Psychiatry, Journal Year: 2024, Volume and Issue: 95(9), P. 822 - 828

Published: Jan. 19, 2024

Background Blood neurofilament light chain (NfL) is increasingly considered as a key trial biomarker in genetic frontotemporal dementia (gFTD). We aimed to facilitate the use of NfL gFTD multicentre trials by testing its (1) reliability across labs; (2) stratify disease stages; (3) comparability between blood matrices and (4) stability recruiting sites. Methods Comparative analysis levels large cohort (GENFI) for (1)–(4), with n=344 samples (n=148 presymptomatic, n=11 converter, n=46 symptomatic subjects, mutations C9orf72 , GRN or MAPT ; n=139 within-family controls), each measured three different international labs Simoa HD-1 analyzer. Results revealed an excellent consistency (intraclass correlation coefficient (ICC) 0.964) high (maximal bias (pg/mL) Bland-Altman analysis: 1.12±1.20). High concordance laboratories was moreover reflected areas under curve discriminating conversion stage against (non-converting) presymptomatic all labs. Serum plasma were largely comparable (ICC 0.967). The robustness 13 sites demonstrated linear mixed effect model. Conclusions Our results underline suitability trials, including cross-lab reliable stratification highly trial-relevant stage, matrix cross-site robustness.

Language: Английский

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Identifying the Phenotypes of Diffuse Axonal Injury Following Traumatic Brain Injury

Brain Sciences, Journal Year: 2023, Volume and Issue: 13(11), P. 1607 - 1607

Published: Nov. 20, 2023

Diffuse axonal injury (DAI) is a significant feature of traumatic brain (TBI) across all severities and driven by the primary mechanical insult secondary biochemical phases. Axons comprise an outer cell membrane, axolemma which anchored to cytoskeletal network with spectrin tetramers actin rings. Neurofilaments act as space-filling structural polymers that surround central core microtubules, facilitate transport. TBI has differential effects on these components, axons in same white matter tract showing range different alterations patterns temporal evolution. These require antibodies for detection post-mortem tissue. Here, comprehensive discussion evolution within elements provided, alongside most appropriate methods their profiles. Accumulation amyloid precursor protein (APP) result disruption transport due microtubule failure remains sensitive marker injury, both acutely chronically. However, subset injured demonstrate pathology, cannot be detected via APP immunoreactivity, including degradation neurofilaments. Furthermore, recent work highlighted node Ranvier axon initial segment particularly vulnerable sites loss sodium channels persisting beyond acute phase post-injury without pathology. Given heterogenous response TBI, further characterization required chronic understand how evolves temporally, may help inform pharmacological interventions.

Language: Английский

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Neurofilament light chain levels in serum among a large mixed memory clinic cohort: Confounders and diagnostic usefulness

Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring, Journal Year: 2023, Volume and Issue: 15(4)

Published: Oct. 1, 2023

Early and accurate diagnosis of neurocognitive disorders including neurodegenerative dementia remains challenging. This study explores the impact biological factors on serum neurofilament light chain (NfL) levels clinical usefulness for detection in a mixed memory clinic.

Language: Английский

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Neurofilament light in serum: reference values and effect of risk factors for multiple sclerosis

Multiple Sclerosis and Related Disorders, Journal Year: 2024, Volume and Issue: 92, P. 106166 - 106166

Published: Nov. 13, 2024

The measurement of neurofilament light (NFL) in blood samples has been established as a sensitive measure neuroaxonal damage wide range diseases the peripheral and central nervous system, including multiple sclerosis (MS). Previous studies have identified confounding factors that may influence serum concentration NFL.

Language: Английский

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Neurofilament heavy phosphorylated epitopes as biomarkers in ageing and neurodegenerative disease

Journal of Neurochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

Abstract From the day we are born, nervous system is subject to insult, disease and degeneration. Aberrant phosphorylation states in neurofilaments, major intermediate filaments of neuronal cytoskeleton, accompany mediate many pathological processes degenerative disease. Neuronal damage, degeneration death can release these internal components extracellular space eventually cerebrospinal fluid blood. Sophisticated assay techniques increasingly able detect their presence at very low levels, increasing utility as biomarkers providing insights differential diagnosis for earliest stages Although a variety studies focus on single or small clusters neurofilament phosphorylated epitopes, this review offers wider perspective landscape heavy subunit, filament component both ageing image

Language: Английский

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