title: Amyloid-β1-42 slows clearance of synaptically released glutamate by mislocalizing astrocytic GLT-1.
abstract: GLT-1, the major glutamate transporter in the adult brain, is abundantly expressed in astrocytic processes enveloping synapses. By limiting glutamate escape into the surrounding neuropil, GLT-1 preserves the spatial specificity of synaptic signaling. Here we show that the amyloid-β peptide Aβ1-42 markedly prolongs the extracellular lifetime of synaptically released glutamate by reducing GLT-1 surface expression in mouse astrocytes and that this effect is prevented by the vitamin E derivative Trolox. These findings indicate that astrocytic glutamate transporter dysfunction may play an important role in the pathogenesis of Alzheimer's disease and suggest possible mechanisms by which several current treatment strategies could protect against the disease.
authors.affiliation: Synaptic Physiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Scimemi
authors.forename: James S
authors.initials: JS
authors.lastname: Meabon
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
authors.forename: Jane M
authors.initials: JM
authors.lastname: Sullivan
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Diamond
authors.forename: David G
authors.initials: DG
authors.lastname: Cook
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism*; D002839:Chromans / Q000494:pharmacology; D004347:Drug Interactions; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009474:Neurons / Q000378:metabolism; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002839:Chromans; D027342:Excitatory Amino Acid Transporter 2; D010446:Peptide Fragments; C493396:Slc1a2 protein, mouse; C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid