Role Of Glucose Transporters In Ischemic Cerebrovascular Diseases And Alzheimer's Disease

PartⅠDecreased Glucose Transporter 1 in Brains with Ischemic CerebrovascularDiseasesObjective To investigate glucose transporter 1 (GLUT1) level in ischemic brain tissueMethods GLUT1 level in the brain of 7 cases with chronic ischemic cerebrovascular diseases (ICVD) and 11 cases of the age-and postmortem interval-matched controls was determined by Western blot.Results GLUT1 level was decreased markedly in ICVD, and this decrease appeared to result from a down-regulation of hypoxia-inducible factor-1α(HIF-la). The level of protein O-GlcNAcylation was not altered in the ICVD brain.Conclusion The decreased GLUT1 level in ischemic brain tissue may be caused by downregulated HIF1α.PartⅡDecreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer diseaseObjective To investigate the relation between GLUTs and hyperphosphorylation of tau in Alzheimer disease brain.Methods GLUT1-4 and GFAP, calbindin, O-GlcNAcylation, tau phosphorylation and HIF-1αlevels were detected in the brain of 7 cases with AD and 7 controls.Results Two major brain glucose transporters (GLUT1 and GLUT3) were decreased in AD brain, which correlated to the decrease in O-GlcNAcylation, to the hyperphosphorylation of tau, and to the density of neurofibrillary tangles in human brains. Down-regulation of hypoxia-inducible factor 1 was seen in AD brain.Conclusion GLUT1 and GLUT3 deficiency could cause impaired brain glucose uptake/metabolism and contribute to neurodegeneration via down-regulation of O- GlcNAcylation and hyperphosphorylation of tau in AD. Decreased GLUT1 and GLUT3 levels may be caused by the down-regultion of HIF-1α.PartⅢBrain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer diseaseObjective To investigate GLUTs level, O-GlcNAcylation and phosphorylation of tau in Type 2 diabetes mellitus (T2DM) and AD brain.Methods The levels of major brain glucose transporters in the postmortem brain tissue from frontal cortices of 7 controls,11 T2DM subjects,10 AD subjects and 8 additional subjects who had both T2DM and AD were determined.Results The neuronal GLUT3 was decreased to a bigger extent in T2DM brain than in AD brain. The O-GlcNAcylation levels of global proteins and of tau were also decreased in T2DM brain as seen in AD brain. Phosphorylation of tau at some of the AD abnormal hyperphosphorylation sites was increased in T2DM brain.Conclusion T2DM may contribute to the increased risk for AD by impairing brain glucose uptake/metabolism and, consequently, down-regulation of O-GlcNAcylation, which facilitates abnormal hyperphosphorylation of tau.