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.
Boado
R J
RJ
Department of Medicine and Brain Research Institute, UCLA School of Medicine, USA.
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