Amyloid-β oligomers in the nucleus accumbens decrease motivation via insertion of calcium-permeable AMPA receptors

Mol Psychiatry. 2022 Apr;27(4):2146-2157. doi: 10.1038/s41380-022-01459-0. Epub 2022 Feb 2.


It is essential to identify the neuronal mechanisms of Alzheimer's Disease (AD)-associated neuropsychiatric symptoms, e.g., apathy, before improving the life quality of AD patients. Here, we focused on the nucleus accumbens (NAc), a critical brain region processing motivation, also known to display AD-associated pathological changes in human cases. We found that the synaptic calcium permeable (CP)-AMPA receptors (AMPARs), which are normally absent in the NAc, can be revealed by acute exposure to Aβ oligomers (AβOs), and play a critical role in the emergence of synaptic loss and motivation deficits. Blockade of NAc CP-AMPARs can effectively prevent AβO-induced downsizing and pruning of spines and silencing of excitatory synaptic transmission. We conclude that AβO-triggered synaptic insertion of CP-AMPARs is a key mechanism mediating synaptic degeneration in AD, and preserving synaptic integrity may prevent or delay the onset of AD-associated psychiatric symptoms.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / metabolism
  • Calcium / metabolism
  • Humans
  • Motivation
  • Nucleus Accumbens / metabolism
  • Receptors, AMPA* / metabolism
  • Receptors, Calcium-Sensing
  • Synapses / metabolism
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid


  • Amyloid beta-Peptides
  • Receptors, AMPA
  • Receptors, Calcium-Sensing
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Calcium