Amyloid-β1-42 Disrupts Synaptic Plasticity by Altering Glutamate Recycling at the Synapse

J Alzheimers Dis. 2015;45(2):449-56. doi: 10.3233/JAD-142367.

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.

Keywords: Alzheimer's disease; NR2B; TBOA; glutamate scavenger; glutamate-reuptake; long-term potentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / pharmacology
  • Amyloid beta-Peptides / pharmacology*
  • Analysis of Variance
  • Animals
  • Aspartic Acid / pharmacology
  • Biophysics
  • Electric Stimulation
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glutamic Acid / metabolism*
  • Hippocampus / cytology
  • In Vitro Techniques
  • Mice
  • Mice, Inbred BALB C
  • Nerve Net / drug effects
  • Neuronal Plasticity / drug effects*
  • Patch-Clamp Techniques
  • Peptide Fragments / pharmacology*
  • Piperidines / pharmacology
  • Pyruvic Acid / pharmacology
  • Synapses / drug effects*

Substances

  • Amyloid beta-Peptides
  • Excitatory Amino Acid Antagonists
  • Peptide Fragments
  • Piperidines
  • amyloid beta-protein (1-42)
  • benzyloxyaspartate
  • Aspartic Acid
  • Glutamic Acid
  • Pyruvic Acid
  • Alanine Transaminase
  • ifenprodil