Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3

Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):E6526-E6534. doi: 10.1073/pnas.1614249113. Epub 2016 Oct 5.

Abstract

Amyloid-β (Aβ) is a prime suspect for causing cognitive deficits during the early phases of Alzheimer's disease (AD). Experiments in AD mouse models have shown that soluble oligomeric clusters of Aβ degrade synapses and impair memory formation. We show that all Aβ-driven effects measured in these mice depend on AMPA receptor (AMPAR) subunit GluA3. Hippocampal neurons that lack GluA3 were resistant against Aβ-mediated synaptic depression and spine loss. In addition, Aβ oligomers blocked long-term synaptic potentiation only in neurons that expressed GluA3. Furthermore, although Aβ-overproducing mice showed significant memory impairment, memories in GluA3-deficient congenics remained unaffected. These experiments indicate that the presence of GluA3-containing AMPARs is critical for Aβ-mediated synaptic and cognitive deficits.

Keywords: AMPA; Alzheimer; amyloid; synapse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / mortality
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Analysis of Variance
  • Animals
  • Behavior, Animal
  • CHO Cells
  • Conditioning, Psychological
  • Cricetulus
  • Dendritic Spines
  • Fear / psychology
  • Female
  • Hippocampus / cytology
  • Hippocampus / physiology
  • Long-Term Potentiation
  • Male
  • Membrane Potentials
  • Memory*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Plaque, Amyloid / genetics
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Pyramidal Cells / cytology
  • Pyramidal Cells / metabolism
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism*
  • Synapses / metabolism*

Substances

  • Amyloid beta-Peptides
  • Receptors, AMPA
  • glutamate receptor ionotropic, AMPA 3