Amyloid beta-peptide inhibits neuronal glucose uptake by preventing exocytosis.
Amyloid beta peptide (Abeta) is suspected as a contributing factor for decreased glucose utilization in the brain of Alzheimer's patients; however, little is known about the regulatory mechanism of neuronal glucose uptake and how Abeta affects such a mechanism. We report that membrane depolarization by 40 mM KCl increases both neuronal glucose uptake and immunolabeling of the exofacial epitope of glucose transporter isoform GLUT3, suggesting that fusion of GLUT3 vesicles with the plasma membrane increases glucose uptake. Abeta25-35 decreased neuronal glucose uptake and this decrease was prevented by exocytosis-enhancing compounds (40 mM KCl, 50 microM ruthenium red). Abeta25-35 also inhibited exocytosis of the fluorescent membrane dye FM1-43 at neuronal cell bodies; however, 40 mM KCl was effective in overcoming this Abeta inhibition. Furthermore, GLUT3 colocalized with SNARE (N-ethylmaleimide-sensitive factor attached protein receptor) complex proteins (SNAP-25 and Syntaxin 1), and cleavage of the v-SNARE, VAMP, reduced glucose uptake. Our findings suggest that neuronal glucose uptake is regulated by SNARE complex-dependent docking and fusion of GLUT3 vesicles with the plasma membrane and that Abeta decreases glucose uptake by inhibiting fusion of these vesicles.
Uemura
E
E
Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
Greenlee
H W
HW
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism*; D005089:Exocytosis / Q000187:drug effects* / Q000502:physiology; D005333:Fetus; D005456:Fluorescent Dyes; D005947:Glucose / Q000378:metabolism*; D051274:Glucose Transporter Type 3; D006624:Hippocampus / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000032:analysis; D009004:Monosaccharide Transport Proteins / Q000032:analysis / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D011726:Pyridinium Compounds; D050765:Qa-SNARE Proteins; D000644:Quaternary Ammonium Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1
D016229:Amyloid beta-Peptides; C073804:FM1 43; D005456:Fluorescent Dyes; D051274:Glucose Transporter Type 3; D008565:Membrane Proteins; D009004:Monosaccharide Transport Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011726:Pyridinium Compounds; D050765:Qa-SNARE Proteins; D000644:Quaternary Ammonium Compounds; C495690:Slc2a3 protein, rat; C494210:Snap25 protein, rat; C494213:Stx1a protein, rat; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; C074636:amyloid beta-protein (25-35); D011189:Potassium Chloride; D003847:Deoxyglucose; D005947:Glucose