title: CREB regulates the expression of neuronal glucose transporter 3: a possible mechanism related to impaired brain glucose uptake in Alzheimer's disease.
abstract: Impaired brain glucose uptake and metabolism precede the appearance of clinical symptoms in Alzheimer disease (AD). Neuronal glucose transporter 3 (GLUT3) is decreased in AD brain and correlates with tau pathology. However, what leads to the decreased GLUT3 is yet unknown. In this study, we found that the promoter of human GLUT3 contains three potential cAMP response element (CRE)-like elements, CRE1, CRE2 and CRE3. Overexpression of CRE-binding protein (CREB) or activation of cAMP-dependent protein kinase significantly increased GLUT3 expression. CREB bound to the CREs and promoted luciferase expression driven by human GLUT3-promoter. Among the CREs, CRE2 and CRE3 were required for the promotion of GLUT3 expression. Full-length CREB was decreased and truncation of CREB was increased in AD brain. This truncation was correlated with calpain I activation in human brain. Further study demonstrated that calpain I proteolysed CREB at Gln28-Ala29 and generated a 41-kDa truncated CREB, which had less activity to promote GLUT3 expression. Importantly, human brain GLUT3 was correlated with full-length CREB positively and with activation of calpain I negatively. These findings suggest that overactivation of calpain I caused by calcium overload proteolyses CREB, resulting in a reduction of GLUT3 expression and consequently impairing glucose uptake and metabolism in AD brain.
authors: Jiangsu Key Laboratory of Neuroregeneration, Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
authors: Nana
authors: N
authors: Jin
authors: Wei
authors: W
authors: Qian
authors: Xiaomin
authors: X
authors: Yin
authors: Lan
authors: L
authors: Zhang
authors: Khalid
authors: K
authors: Iqbal
authors: Inge
authors: I
authors: Grundke-Iqbal
authors: Cheng-Xin
authors: CX
authors: Gong
authors: Fei
authors: F
authors: Liu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D001483:Base Sequence; D002154:Calpain / Q000737:chemistry / Q000378:metabolism; D016022:Case-Control Studies; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D051274:Glucose Transporter Type 3 / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D051274:Glucose Transporter Type 3; D010446:Peptide Fragments; D012333:RNA, Messenger; C495687:SLC2A3 protein, human; D049410:Luciferases, Renilla; D017868:Cyclic AMP-Dependent Protein Kinases; D002154:Calpain