Molecular regulation of the blood-brain barrier GLUT1 glucose transporter by brain-derived factors.
Glucose is the crucial metabolic fluid for the brain, and the transport of this nutrient from blood to brain is limited by the blood-brain barrier (BBB) GLUT1 glucose transporter. The activity of this transporter is altered in different pathophysiological conditions including Alzheimer's disease. The expression of the BBB-GLUT1 gene is directed by brain trophic factors, and the brain-derived peptide preparation Cerebrolysin (Cl, EBEWE, Austria), used in the treatment of Alzheimer's disease, increases the BBB-GLUT1 mRNA stability and the expression of the BBB-GLUT1 gene. In the present investigation, Cl markedly increased (p < 0.001) the expression of a BBB-GLUT1 reporter gene, named clone 753, that contains an important regulatory cis-acting element involved in the stabilization of this transcript in brain endothelial cultured cells (ECL). In experiments with a reporter gene lacking this regulatory element, Cl produced only a minimal fraction of the effect observed with clone 753. UV-cross linking/PAGE experiments showed that the GLUT1 transcript reacts with ECL cytosolic proteins to form a RNA/protein complex of approximately 80 kDa. The abundance of this cis/trans acting complex was found to be increased in Cl-treated cells. Overall, data presented here demonstrate that i) Cl increases the expression of a BBB-GLUT1-luciferase reporter gene containing a region of the 3'-untranslated region of BBB-GLUT1 mRNA with important regulatory cis-acting elements involved in the stabilization of this transcript, and ii) the increased expression of this BBB-GLUT1 reporter gene was associated with augmented abundance of a transacting factor that binds to the cis-acting element described in (i), suggesting that this association may be involved in the stabilization of GLUT1 mRNA induced by Cl.
Department of Medicine and Brain Research Institute, UCLA School of Medicine, USA.
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Boado
D020413:3' Untranslated Regions / Q000096:biosynthesis / Q000235:genetics; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D002417:Cattle; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D018697:Nootropic Agents / Q000494:pharmacology*; D051381:Rats; D014162:Transfection; D014466:Ultraviolet Rays
D020413:3' Untranslated Regions; D000596:Amino Acids; D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; D018697:Nootropic Agents; C495679:Slc2a1 protein, rat; C006952:cerebrolysin; D005947:Glucose