Annabella Pignataro1, Giovanni Meli2, Roberto Pagano3, Veronica Fontebasso4, Roberta Battistella5, Giulia Conforto6, Martine Ammassari-Teule1, Silvia Middei7. 1. Laboratory of Psychobiology, Department of Experimental Neurology, Santa Lucia Foundation, Rome, Italy; Institute of Cell Biology and Neurobiology, National Research Council, Rome, Italy. 2. European Brain Research Institute-Fondazione Rita Levi Montalcini, Rome, Italy. Electronic address: g.meli@ebri.it. 3. Department of Molecular and Cellular Neurobiology Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland. 4. Department of Pharmacology & Toxicology and Center for Chemistry and Biomedicine, University of Innsbruck, Innsbruck, Austria. 5. Department of Experimental Biomedical Sciences, Lund University, Lund, Sweden. 6. Laboratory of Psychobiology, Department of Experimental Neurology, Santa Lucia Foundation, Rome, Italy. 7. Institute of Cell Biology and Neurobiology, National Research Council, Rome, Italy. Electronic address: silvia.middei@cnr.it.
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.
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.
Authors: Joseph A McQuail; Amy R Dunn; Yaakov Stern; Carol A Barnes; Gerd Kempermann; Peter R Rapp; Catherine C Kaczorowski; Thomas C Foster Journal: Front Aging Neurosci Date: 2021-01-21 Impact factor: 5.750