The Amyloid Precursor Protein C-Terminal Domain Alters CA1 Neuron Firing, Modifying Hippocampus Oscillations and Impairing Spatial Memory Encoding

Cell Rep. 2019 Oct 8;29(2):317-331.e5. doi: 10.1016/j.celrep.2019.08.103.


There is a growing consensus that Alzheimer's disease (AD) involves failure of the homeostatic machinery, which underlies the firing stability of neural circuits. What are the culprits leading to neuron firing instability? The amyloid precursor protein (APP) is central to AD pathogenesis, and we recently showed that its intracellular domain (AICD) could modify synaptic signal integration. We now hypothesize that AICD modifies neuron firing activity, thus contributing to the disruption of memory processes. Using cellular, electrophysiological, and behavioral techniques, we show that pathological AICD levels weaken CA1 neuron firing activity through a gene-transcription-dependent mechanism. Furthermore, increased AICD production in hippocampal neurons modifies oscillatory activity, specifically in the γ-frequency range, and disrupts spatial memory task. Collectively, our data suggest that AICD pathological levels, observed in AD mouse models and in human patients, might contribute to progressive neuron homeostatic failure, driving the shift from normal aging to AD.

Keywords: AICD; APP; Alzheimer’s disease; brain oscillations; memory encoding; neuron firing.

MeSH terms

  • Action Potentials / physiology*
  • Amyloid beta-Protein Precursor / chemistry*
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • CA1 Region, Hippocampal / physiology*
  • Calcium Channels / metabolism
  • Gamma Rhythm / physiology
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Models, Biological
  • Neurons / physiology*
  • Potassium Channels / metabolism
  • Protein Domains
  • Rats, Sprague-Dawley
  • Spatial Memory / physiology*
  • Structure-Activity Relationship
  • Transcription, Genetic


  • Amyloid beta-Protein Precursor
  • Calcium Channels
  • Potassium Channels