P2‐081: CREB regulates the expression of neuronal glucose transporter 3: A mechanism leading to impaired brain glucose uptake in Alzheimer's disease
Year: 2012
Type: article
Abstract: Brain glucose uptake/metabolism is impaired in Alzheimer's disease (AD). Glucose can not be synthesized or stored in brain neurons that fully depend on glucose transport facilitated by glucose transporters (GLUTs) across the blood-brain barrier and cell membrane. There are 14 members of GLUTs reported in the literature. GLUT3 is the major neuronal glucose transporter. Previous studies reported that GLUT3 is decreased and this decrease is correlated to the decrease in O-GlcNAcylation and to the hyperphosphorylation of tau in AD brain. The cause of the decreased GLUT3 in AD brain is unknown. We first analyzed the promoter of human GLUT3 gene by Matlnspector software analysis. We investigated the effect of CREB on human GLUT3 transcription expression by electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and luciferase reporter. The protein levels of calpain I and CREB in AD and control brains were determined by Western blots. The proteolysis of CREB by calpain I was carried out in vitro. We found that the promoter of human GLUT3 contains three CREs, named CRE1, CRE2, and CRE3. CREB bound to these three CREs and promoted the luciferase activity driven by the GLUT3 promoter. By employing serial deletion and site mutations, we identified that CRE2 and CRE3 were required for the promotion of GLUT3 expression. In AD brain, the truncation of CREB from 45 kDa into 41 kDa was significantly increased and correlated with the overactivation of calpain I. Calpain I cleaved CREB at the N-terminus in vitro and generated the truncated CREB, which was less active than the full-length CREB to promote GLUT3 expression. Truncation of CREB was negatively correlated with the level of GLUT3 in human brain. These findings suggest that overactivation of calpain I probably due to calcium overload in AD brain cleaves CREB at the N-terminus and down-regulated the expression of GLUT3, leading to decreased glucose uptake and O-GlcNAcylation of tau and, consequently, tau hyperphosphorylation and neurodegeneration in AD brain.
Source: Alzheimer s & Dementia
Institution: Nantong University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1975367422