Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions

Abstract

To ensure efficient energy supply to the high demanding brain, nutrients are transported into brain cells via specific glucose (GLUT) and monocarboxylate transporters (MCT). Mitochondrial dysfunction and altered glucose metabolism are thought to play an important role in the progression of neurodegenerative diseases, including multiple sclerosis (MS). Here, we investigated the cellular localization of key GLUT and MCT proteins in human brain tissue of non-neurological controls and MS patients. We show that in control brain tissue GLUT and MCT proteins were abundantly expressed in a variety of central nervous system cells, particularly in microglia and endothelial cells. In active MS lesions, GLUTs and MCTs were highly expressed in infiltrating leukocytes and reactive astrocytes. Astrocytes manifest increased MCT1 staining and maintain GLUT expression in inactive lesions, whereas demyelinated axons exhibit significantly reduced GLUT3 and MCT2 immunoreactivity in inactive lesions. Finally, we demonstrated that the co-transcription factor peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), an important protein involved in energy metabolism, is highly expressed in reactive astrocytes in active MS lesions. Overexpression of PGC-1α in astrocyte-like cells resulted in increased production of several GLUT and MCT proteins. In conclusion, we provide for the first time a comprehensive overview of key nutrient transporters in white matter brain samples. Moreover, our data demonstrate an altered expression of these nutrient transporters in MS brain tissue, including a marked reduction of axonal GLUT3 and MCT2 expression in chronic lesions, which may impede efficient nutrient supply to the hypoxic demyelinated axons thereby contributing to the ongoing neurodegeneration in MS.

Insulin and Insulin-like Growth Factor 1 (IGF-1) Modulate Cytoplasmic Glucose and Glycogen Levels but Not Glucose Transport across the Membrane in Astrocytes

“…It has also been found in forebrain microvascular endothelium (70) and in vascular structures within the ventromedial hypothalamus, which suggests that GLUT4 may have a functional role in the blood-brain barrier (71). A recent study indicates that cultured astrocytes also express GLUT4 (59). Stimulation of astrocytes with insulin in an experiment in which we intermittently superfused cells with extracellular solution containing either high concentration of D-glucose or no glucose resulted in equal dynamics of the intracellular glucose changes compared with experiments where cells were not treated with insulin (Fig.…”

“…However, the mechanism by which insulin and IGF-1 modulate glycogen stores in astrocytes is still poorly understood, and it is only speculated that insulin stimulation regulates glucose uptake into astrocytes (23,58). The uptake may involve glucose transporter GLUT4, the expression of which in astrocytes was recently confirmed with immunocytochemical staining (59). In the present study, we have addressed this question using a glucose nanosensor based on FRET, which allows high temporal resolution measurement of the dynamic glucose concentration in single cells (60).…”

Oligodendroglia: metabolic supporters of neurons

“…Changes in MCT expression have been observed in MS patients. MCT1 expression seems to be upregulated in active MS lesions in astrocytes, whereas neuronal MCT2 is markedly downregulated, which could profoundly impede metabolic support to neurons (96). In addition, changes in astrocyte/oligodendrocyte connexins have been reported in MS patients and in MS animal models (97)(98)(99): In MS patients, Cx32 and Cx47 gap junctions are downregulated, while Cx43 expression is upregulated.…”

Astrocytic transporters in Alzheimer's disease

“…The brain accounts for at least 20% of whole body glucose utilisation (85). A summary of the cellular expression of the main glucose and MCTs in human and rodent CNS is provided by Nijland et al (2014). The glucose transporter GLUT1 (SLC2A1)…”