Abstract

IntroductionDemyelinated axons in multiple sclerosis (MS) lesions have an increased energy demand in order to maintain conduction. However, oxidative stress-induced mitochondrial dysfunction likely alters glucose metabolism and consequently impairs neuronal function in MS. Imaging and pathological studies indicate that glucose metabolism is altered in MS, although the underlying mechanisms and its role in neurodegeneration remain elusive. We investigated expression patterns of key enzymes involved in glycolysis, tricarboxylic acid (TCA) cycle and lactate metabolism in well-characterized MS tissue to establish which regulators of glucose metabolism are involved in MS and to identify underlying mechanisms.ResultsExpression levels of glycolytic enzymes were increased in active and inactive MS lesions, whereas expression levels of enzymes involved in the TCA cycle were upregulated in active MS lesions, but not in inactive MS lesions. We observed reduced expression and production capacity of mitochondrial α-ketoglutarate dehydrogenase (αKGDH) in demyelinated axons, which correlated with signs of axonal dysfunction. In inactive lesions, increased expression of lactate-producing enzymes was observed in astrocytes, whereas lactate-catabolising enzymes were mainly detected in axons. Our results demonstrate that the expression of various enzymes involved in glucose metabolism is increased in both astrocytes and axons in active MS lesions. In inactive MS lesions, we provide evidence that astrocytes undergo a glycolytic shift resulting in enhanced astrocyte-axon lactate shuttling, which may be pivotal for the survival of demyelinated axons.ConclusionIn conclusion, we show that key enzymes involved in energy metabolism are differentially expressed in active and inactive MS lesions. Our findings imply that, in addition to reduced oxidative phosphorylation activity, other bioenergetic pathways are affected as well, which may contribute to ongoing axonal degeneration in MS.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0261-8) contains supplementary material, which is available to authorized users.

Highlights

  • Demyelinated axons in multiple sclerosis (MS) lesions have an increased energy demand in order to maintain conduction

  • Expression levels of glycolytic enzymes were increased in active and inactive MS lesions, whereas expression levels of enzymes involved in the tricarboxylic acid (TCA) cycle were upregulated in active MS lesions, but not in inactive MS lesions

  • Our results demonstrate that the expression of various enzymes involved in glucose metabolism is increased in both astrocytes and axons in active MS lesions

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Summary

Introduction

Demyelinated axons in multiple sclerosis (MS) lesions have an increased energy demand in order to maintain conduction. Oxidative stress-induced mitochondrial dysfunction likely alters glucose metabolism and impairs neuronal function in MS. Imaging and pathological studies indicate that glucose metabolism is altered in MS, the underlying mechanisms and its role in neurodegeneration remain elusive. Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system where macrophages and Tcells infiltrate the brain and induce widespread demyelination [15]. Glucose and lactate levels are increased in MS lesions, as determined with positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) [39, 40]. There is ample evidence that glucose metabolism is altered in MS brain tissue and may play an important role in driving neurodegeneration

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