Activity-Induced Amyloid-β Oligomers Drive Compensatory Synaptic Rearrangements in Brain Circuits Controlling Memory of Presymptomatic Alzheimer's Disease Mice

Annabella Pignataro, Giovanni Meli, Roberto Pagano, Veronica Fontebasso, Roberta Battistella, Giulia Conforto, Martine Ammassari-Teule, Silvia Middei

Research output: Contribution to journalArticle

Abstract

Background: A consistent proportion of individuals at risk for Alzheimer's disease show intact cognition regardless of the extensive accumulation of amyloid-β (Aβ) peptide in their brain. Several pieces of evidence indicate that overactivation of brain regions negative for Aβ can compensate for the underactivation of Aβ-positive ones to preserve cognition, but the underlying synaptic changes are still unexplored. Methods: Using Golgi staining, we investigate how dendritic spines rearrange following contextual fear conditioning (CFC) in the hippocampus and amygdala of presymptomatic Tg2576 mice, a genetic model for Aβ accumulation. A molecular biology approach combined with intrahippocampal injection of a γ-secretase inhibitor evaluates the impact of Aβ fluctuations on spine rearrangements. Results: Encoding of CFC increases Aβ oligomerization in the hippocampus but not in the amygdala of Tg2576 mice. The presence of Aβ oligomers predicts vulnerability to network dysfunctions, as low c-Fos activation and spine maturation are detected in the hippocampus of Tg2576 mice upon recall of CFC memory. Rather, enhanced c-Fos activation and new spines are evident in the amygdala of Tg2576 mice compared with wild-type control mice. Preventing Aβ increase in the hippocampus of Tg2576 mice restores CFC-associated spine changes to wild-type levels in both the hippocampus and amygdala. Conclusions: Our study provides the first evidence of neural compensation consisting of enhanced synaptic activity in brain regions spared by Aβ load. Furthermore, it unravels an activity-mediated feedback loop through which neuronal activation during CFC encoding favors Aβ oligomerization in the hippocampus and prevents synaptic rearrangements in this region.

Original languageEnglish
JournalBiological Psychiatry
DOIs
Publication statusAccepted/In press - Jan 1 2018

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Keywords

  • Alzheimer disease
  • Amygdala
  • Aβ oligomers
  • Contextual fear conditioning
  • Hippocampus
  • Neural compensation

ASJC Scopus subject areas

  • Biological Psychiatry

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