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

Background: A consistent proportion of individuals at risk for Alzheimer's disease show intact cognition regardless of the extensive accumulation of amyloid-? (A?) peptide in their brain. Several pieces of evidence indicate that overactivation of brain regions negative for A? can compensate for the underactivation of A?-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 A? accumulation. A molecular biology approach combined with intrahippocampal injection of a ?-secretase inhibitor evaluates the impact of A? fluctuations on spine rearrangements. Results: Encoding of CFC increases A? oligomerization in the hippocampus but not in the amygdala of Tg2576 mice. The presence of A? 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 A? 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 A? load. Furthermore, it unravels an activity-mediated feedback loop through which neuronal activation during CFC encoding favors A? oligomerization in the hippocampus and prevents synaptic rearrangements in this region.