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Cited by 51Advanced Glycation End Products researchMultiple Sclerosis Research StudiesNeuroinflammation and Neurodegeneration Mechanisms

Methylglyoxal-Derived Advanced Glycation Endproducts Accumulate in Multiple Sclerosis Lesions

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Wetzels, Suzan, Vanmierlo, Tim, Scheijen, Jean L. J. M., van Horssen, Jack, Amor, Sandra, Somers, Veerle, Schalkwijk, Casper G., Hendriks, Jerome J. A. +1 more·2019·Frontiers in Immunology
DOI 10.3389/fimmu.2019.00855PMC PMC6491451
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Abstract

Multiple sclerosis (MS) is a demyelinating autoimmune disease in which innate and adaptive immune cells infiltrate the central nervous system (CNS) and damage the myelin sheaths surrounding the axons. Upon activation, infiltrated macrophages, CNS-resident microglia and astrocytes switch their metabolism towards glycolysis, resulting in the formation of α-dicarbonyls, such as methylglyoxal (MGO) and glyoxal (GO). These potent glycating agents lead to the formation of advanced glycation endproducts (AGEs) after reaction with amino acids. We hypothesize that AGE levels are increased in MS lesions due to the inflammatory activation of macrophages and astrocytes. First, we measured tissue levels of AGEs in brain samples of MS patients and controls. Analysis of MS patient and non-demented control (NDC) specimens showed a significant increase in protein-bound Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), the major AGE, compared to white matter of NDCs (107 ± 11 vs 154 ± 21, p<0.05). In addition, immunohistochemistry revealed that MGO-derived AGEs were specifically present in astrocytes, whereas the receptor for AGEs, RAGE, was detected on microglia/macrophages. Moreover, in cerebrospinal fluid from MS patients, α-dicarbonyls and free AGEs correlated with their respective levels in the plasma, whereas this was not observed for protein-bound AGEs. Taken together, our data show that MG-H1 is produced by astrocytes. This suggests that AGEs secreted by astrocytes have paracrine effects on RAGE-positive macrophages/microglia and thereby contribute to the pathology of MS.

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  • Plasma free and protein-bound CML levels did not differ between multiple sclerosis patients (n = 15) and non-demented controls (n = 10), measured by UPLC-MS/MS.

    “| Multiple sclerosis | CSF, plasma, brain tissue | Non-demented control subjects (n = 10) vs. multiple sclerosis patients (n = 15) | UPLC-MS/MS,IHC | No difference in plasma free and protein-bound CML levels | [168] |”

    From Protein oxidation - Formation mechanisms, detection and relevance as biomarkers in human diseases (2021) · cites this paper as [168]

    The Results section ('MG-H1 Is Increased in the Lesion Area of MS Patients'; page unavailable) reports no difference in free or protein-bound CML between MS lesions and control brain tissue, using samples from 15 MS patients and 10 non-demented controls. The Methods ('α-Dicarbonyl and AGE Measurements'; page unavailable) confirm UPLC-MS/MS measurement, but the plasma samples came from 18 MS patients and were analyzed for plasma–CSF correlations, not compared with those controls. The claimed absence of a difference in plasma CML is therefore unsupported. (LLM, conf=0.89)

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Authors
Wetzels, S., Vanmierlo, T., Scheijen, J. L. J. M., van Horssen, J., Amor, S., Somers, V., Schalkwijk, C. G., Hendriks, J. J. A., & Wouters, K.
Affiliations
  • Maastricht University (NL)
  • Amsterdam University Medical Centers (NL)
  • Hasselt University (BE)
Corresponding author
Wouters, Kristiaan
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2019-04-24
Volume
10
Pages
855-855
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2019.00855
PMC
PMC6491451
OpenAlex
W2942312619
Cited by
51
References
6
Citations by year
2026: 7 · 2025: 6 · 2024: 3 · 2023: 8 · 2022: 7 · 2021: 14 · 2020: 5 · 2019: 1
FWCI
4.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, cc-by)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Document Server@UHasselt (UHasselt) (submittedVersion, cc-by)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • Universiteit Hasselt
  • Bijzonder Onderzoeksfonds UGent
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
multiple sclerosis, advanced glycation end products, methylglyoxal, MG-H1, glyoxal, α-dicarbonyl compounds, astrocytes, microglia, macrophages, receptor for advanced glycation end products, demyelination, neuroinflammation, cerebrospinal fluid biomarkers, paracrine signaling, white matter lesions
MeSH terms
Aged, Astrocytes, Disease Susceptibility, Female, Humans, Immunohistochemistry, Male, Middle Aged, Multiple Sclerosis, Pyruvaldehyde, Biomarkers, Glycation End Products, Advanced, Microglia, Disease Progression

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