Abstract
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). The activation of inflammatory cells is crucial for the development of MS and is shown to induce intracellular glycolytic metabolism in pro-inflammatory microglia and macrophages, as well as CNS-resident astrocytes. Advanced glycation endproducts (AGEs) are stable endproducts formed by a reaction of the dicarbonyl compounds methylglyoxal (MGO) and glyoxal (GO) with amino acids in proteins, during glycolysis. This suggests that, in MS, MGO-derived AGEs are formed in glycolysis-driven cells. MGO and MGO-derived AGEs can further activate inflammatory cells by binding to the receptor for advanced glycation endproducts (RAGE). Recent studies have revealed that AGEs are increased in the plasma and brain of MS patients. Therefore, AGEs might contribute to the inflammatory status in MS. Moreover, the main detoxification system of dicarbonyl compounds, the glyoxalase system, seems to be affected in MS patients, which may contribute to high MGO-derived AGE levels. Altogether, evidence is emerging for a contributing role of AGEs in the pathology of MS. In this review, we provide an overview of the current knowledge on the involvement of AGEs in MS.
Highlights
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) [1]
The frequency of the EE genotype, which has the glutamic acid on both chromosomes, was significantly increased in RR-MS patients compared to controls (59.8% vs. 49.3%, p < 0.0001) [57], suggesting that decreased Glo-1 activity can contribute to increased MGO-derived Advanced glycation endproducts (AGEs)-levels in MS patients, compared to controls
Several studies found increased AGE levels in the CNS of MS patients, and there is plenty of evidence that glycolysis and lipid peroxidation are increased in MS
Summary
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) [1]. The autoimmune response, which mainly involves autoreactive T-lymphocytes, macrophages, and CNS-resident microglia, is directed against CNS antigens [13]. Macrophages and microglia contribute to neuroinflammation and neurodegeneration by the secretion of pro-inflammatory mediators such as cytokines and chemokines, the degradation and phagocytosis of myelin, and the presentation of myelin antigens to autoreactive T-lymphocytes [13]. The second, opposing, hypothesis states that an initiating event within the CNS, a primary infection or neuronal disturbances, causes the activation of resident microglia, and is called the “inside-out hypothesis” [16]. This immune reaction in the CNS leads to the recruitment of innate and adaptive immune cells from the periphery, which aggravates CNS inflammation.
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