Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease 1 Ying Liu a,b , Fei Liu a , Khalid Iqbal a , Inge Grundke-Iqbal a , and Cheng-Xin Gong a,* aDepartment of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA bRenmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang District, Wuhan, Hubei 430060, P.R. China Abstract Brain glucose uptake/metabolism is impaired in Alzheimer disease (AD). Here, we report that levels of the two major brain glucose transporters (GLUT1 and GLUT3) responsible for glucose uptake into neurons were decreased in AD brain. This decrease correlated to the decrease in O- GlcNAcylation, to the hyperphosphorylation of tau, and to the density of neurofibrillary tangles in human brains. We also found down-regulation of hypoxia-inducible factor 1, a major regulator of GLUT1 and GLUT3, in AD brain. These studies provide a possible mechanism by which 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. Keywords Glucose transporters; tau; hyperphosphorylation; Alzheimer disease; O-GlcNAcylation; hypoxia- inducible factor 1. Introduction Alzheimer disease (AD) is characterized histopathologically by extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs). The number of tangles in the brain correlates to dementia symptoms [1–3], suggesting that neurofibrillary degeneration may contribute to the pathogenesis of AD. NFTs are mainly composed of abnormally hyperphosphorylated tau that aggregates into paired helical filaments and straight filaments [4]. Many studies have demonstrated that abnormal hyperphosphorylation of tau is crucial to neurodegeneration [5, 6]. Although extensive studies have been carried out on protein kinases and phosphatases that regulate tau phosphorylation, the mechanisms leading to the abnormal hyperphosphorylation of tau in AD brain are not well understood. 1 Abbreviations used. AD, Alzheimer disease; GFAP, glial fibrillary acid protein; GlcNAc, β-N-acetylglucosamine; GLUTs, glucose transporters; HIF-1, hypoxia-inducible factor 1; NFTs, neurofibrillary tangles. * Corresponding Author. Address: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314-6399, USA. Phone: 1-718-494-5248; Fax: 1-718-494-1080; E-mail: cxgong@mail.csi.cuny.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript FEBS Lett. Author manuscript; available in PMC 2008 February 19. Published in final edited form as: FEBS Lett. 2008 January 23; 582(2): 359–364. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript