Amyloid β-Peptide Decreases Neuronal Glucose Uptake Despite Causing Increase in GLUT3 mRNA Transcription and GLUT3 Translocation to the Plasma Membrane

Abstract

Amyloid β-peptide (Aβ) has been shown to impair glucose uptake in cultured hippocampal neurons and shortens their survival time. Aβ appears to inhibit neuronal glucose uptake by activating Gs-coupled receptors and the cAMP-PKA system. In this study, Aβ inhibition of neuronal glucose uptake was studied by assaying translocation of glucose transporter isoform GLUT3, transcription of GLUT3 mRNA, and fusion of GLUT3-containing vesicles with the plasma membrane. Cultured hippocampal neurons exposed to 10 μM Aβ25–35 or Aβ1–40 for 3 or 24 h showed a significant decrease in glucose uptake. To assess the regulatory role of Aβ on neuronal glucose uptake, translocation of GLUT3 from the cytosol to the plasma membrane was studied by the plasma membrane lawn assay and transcription of GLUT3 mRNA by in situ hybridization. In spite of a decrease in glucose uptake, Aβ25–35 and Aβ1–40 (10 μM) markedly promoted GLUT3 translocation to the plasma membrane by 30 min. Aβ25–35 also up-regulated transcription of GLUT3 mRNA by 12 h. High extracellular K+ increased immunolabeling of the exofacial (i.e., extracellular) epitope of GLUT3 at the plasma membrane and Aβ25–35 inhibited this increase. Based on these data we propose that Aβ increases translocation of GLUT3-containing vesicles, but inhibits their fusion with the plasma membrane.