Alzheimer's disease severity is associated with a progressive decline in GLUT1 gene expression: Role of posttranscriptional regulation

Numerous positron emission tomography (PET) studies have demonstrated in vivo that glucose transport is decreased in the brains of patients afflicted with Alzheimer's Disease (AD). Glucose is the primary energy source for mammalian brain, and a continuous supply of this substrate is essential to cerebral function. Glucose crosses the endothelial cells of the blood-brain barrier and the cell membranes of astrocytes exclusively via glucose transporter protein 1 (GLUT1), and represents the major route of entry for glucose into the brain. The density and kinetic properties of GLUT1 transporters have previously been shown to determine the rate of glucose transport, and there is evidence that brain metabolism can potentially be rate-limited by GLUT1 activity.;A growing number of mRNAs appear to be regulated by ribonuclear binding protein(s) (RBP), and complex formation of an RBP with an AU-rich motif in the 3' untranslated region (3'-UTR) of an mRNA molecule can result in increased mRNA stability. The body of work detailed in this thesis focuses on the posttranscriptional regulation of GLUT1 gene expression via the complex formation between RBP and a UAUUUAUA motif in the 3'-UTR of GLUT1 mRNA. The data suggest that this process is progressively dysfunctional in AD of increasing severity. It is therefore hypothesized that the mechanism causing or exacerbating the decreased glucose transport and glucose metabolism observed in AD brain is a decrease in complex formation between an RBP and GLUT1 mRNA, causing a decline in GLUT1 gene expression. The studies described examine this regulation of GLUT1 gene expression in tissue, matched for both age and postmortem delay, from identical regions of normal and Alzheimer brains of progressive disease severity (mild, moderate, severe) and demonstrate that GLUT1 gene expression decreases progressively as AD severity increases, and that there is a concomitant progressive decrease in complex formation between the RBP(s) and the 3'-UTR of GLUT1 mRNA. This work contributes to our knowledge of a possible mechanism underlying the altered glucose transport in AD, and presents a potential target for therapeutic intervention.