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|Title: ||Methylglyoxal-Derived Advanced Glycation Endproducts Accumulate in Multiple Sclerosis Lesions|
|Authors: ||Wetzels, Suzan|
Scheijen, Jean L. J. M.
van Horssen, Jack
Schalkwijk, Casper G.
Hendriks, Jerome J. A.
|Issue Date: ||2019|
|Publisher: ||FRONTIERS MEDIA SA|
|Citation: ||FRONTIERS IN IMMUNOLOGY, 10 (Art N° 855)|
|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.|
|Notes: ||[Wetzels, Suzan; Scheijen, Jean L. J. M.; Schalkwijk, Casper G.; Wouters, Kristiaan] Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Internal Med, Maastricht, Netherlands. [Wetzels, Suzan; Vanmierlo, Tim; Somers, Veerle; Hendriks, Jerome J. A.] Hasselt Univ, Dept Immunol & Biochem, Biomed Res Inst, Hasselt, Belgium. [Vanmierlo, Tim] Maastricht Univ, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands. [van Horssen, Jack] Vrije Univ, Amsterdam UMC, Dept Mol Cell Biol & Immunol, Amsterdam, Netherlands. [Amor, Sandra] Vrije Univ Amsterdam Med Ctr, Amsterdam UMC, Dept Pathol, Amsterdam, Netherlands.|
|ISI #: ||000465392700001|
|Type: ||Journal Contribution|
|Appears in Collections: ||Research publications|
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