title: Amyloid-β1-42 Disrupts Synaptic Plasticity by Altering Glutamate Recycling at the Synapse.
abstract: Alzheimer's disease (AD) is the most prevalent form of neurodegenerative disorders characterized by neuritic plaques containing amyloid-β peptide (Aβ) and neurofibrillary tangles. Evidence has been reported that Aβ(1-42) plays an essential pathogenic role in decreased spine density, impairment of synaptic plasticity, and neuronal loss with disruption of memory-related synapse function, all associated with AD. Experimentally, Aβ(1-42) oligomers perturb hippocampal long-term potentiation (LTP), an electrophysiological correlate of learning and memory. Aβ was also reported to perturb synaptic glutamate (Glu)-recycling by inhibiting excitatory-amino-acid-transporters. Elevated level of extracellular Glu leads to activation of perisynaptic receptors, including NR2B subunit containing NMDARs. These receptors were shown to induce impaired LTP and enhanced long-term depression and proapoptotic pathways, all central features of AD. In the present study, we investigated the role of Glu-recycling on Aβ(1-42)-induced LTP deficit in the CA1. We found that Aβ-induced LTP damage, which was mimicked by the Glu-reuptake inhibitor TBOA, could be rescued by blocking the NR2B subunit of NMDA receptors. Furthermore, decreasing the level of extracellular Glu using a Glu scavenger also restores TBOA or Aβ induces LTP damage. Overall, these results suggest that reducing ambient Glu in the brain can be protective against Aβ-induced synaptic disruption.
authors.affiliation: Department of Medical Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: Edina
authors.initials: E
authors.lastname: Varga
authors.affiliation: Department of Medical Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Juhász
authors.affiliation: Department of Medical Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bozsó
authors.affiliation: Department of Medical Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: Botond
authors.initials: B
authors.lastname: Penke
authors.affiliation: Department of Medical Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: Lívia
authors.initials: L
authors.lastname: Fülöp
authors.affiliation: Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Viktor
authors.initials: V
authors.lastname: Szegedi
mesh_terms: D000410:Alanine Transaminase / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D001703:Biophysics; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D009415:Nerve Net / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D019289:Pyruvic Acid / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D010880:Piperidines; C075222:amyloid beta-protein (1-42); C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; D019289:Pyruvic Acid; D000410:Alanine Transaminase; C010739:ifenprodil
keywords: Alzheimer's disease; NR2B; TBOA; glutamate scavenger; glutamate-reuptake; long-term potentiation