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 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.
Highlights
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) and is the major cause of disability in young adults in Western countries [1]
To determine whether the levels of α-dicarbonyls and advanced glycation endproducts (AGEs) are increased in the lesions of MS patients compared to white matter of nondemented controls (NDCs), post-mortem lesions of 15 MS patients and 10 white matter samples of NDCs were obtained (Table 1) and levels of MGO, GO and free and protein-bound CML, CEL, and MG-H1 were measured
In this study we showed that MGO-derived MG-H1 is significantly increased in MS lesions and is mostly present in astrocytes
Summary
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) and is the major cause of disability in young adults in Western countries [1]. The exact trigger of MS remains unidentified, an autoimmune response against the myelin sheaths is widely-considered involved in disease onset and progression. This autoimmune response is caused by an interplay. Most patients (85%) present with the relapsingremitting MS disease course in which relapses result in episodes of disability with full recovery between the relapses [1]. Over half of these patients enter the secondary progressive phase after 5–15 year of diagnosis which is characterized by progression of the disease without full recovery caused by axonal damage [5]
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