Methylglyoxal-Derived Advanced Glycation Endproducts Accumulate in Multiple Sclerosis Lesions

Suzan Wetzels, Tim Vanmierlo, Jean L. J. M. Scheijen, Jack van Horssen, Sandra Amor, Veerle Somers, Casper G. Schalkwijk, Jerome J. A. Hendriks, Kristiaan Wouters*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

23 Citations (Web of Science)

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 toward glycolysis, resulting in the formation of alpha-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 Nd-(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, alpha-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.

Original languageEnglish
Article number855
Number of pages9
JournalFrontiers in Immunology
Volume10
DOIs
Publication statusPublished - 24 Apr 2019

Keywords

  • multiple sclerosis
  • neuroinflammation
  • alpha-dicarbonyl
  • advanced glycation endproducts
  • astrocytes
  • END-PRODUCTS AGES
  • CEREBROSPINAL-FLUID
  • GENE-EXPRESSION
  • CHOROID-PLEXUS
  • DISEASE
  • INDIVIDUALS
  • MECHANISMS
  • OXIDATION
  • BIOMARKER
  • RECEPTOR

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