title: 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.
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Nijland
authors.forename: Iliana
authors.initials: I
authors.lastname: Michailidou
authors.forename: Maarten E
authors.initials: ME
authors.lastname: Witte
authors.forename: Mark R
authors.initials: MR
authors.lastname: Mizee
authors.forename: Susanne M A
authors.initials: SM
authors.lastname: van der Pol
authors.forename: Bert
authors.initials: B
authors.lastname: van Het Hof
authors.forename: Arie
authors.initials: A
authors.lastname: Reijerkerk
authors.forename: Luc
authors.initials: L
authors.lastname: Pellerin
authors.forename: Paul
authors.initials: P
authors.lastname: van der Valk
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001369:Axons / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology; D020528:Multiple Sclerosis, Chronic Progressive / Q000378:metabolism / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000378:metabolism; D066127:White Matter / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology
chemical_list: D051274:Glucose Transporter Type 3; D050491:Glutamate Plasma Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C490427:SLC16A7 protein, human; C495687:SLC2A3 protein, human; D014157:Transcription Factors
keywords: neurodegeneration; nutrient transporters; proliferator-activated receptor gamma co-activator 1-alpha; reactive astrocytes