Activity-Induced Amyloid-β Oligomers Drive Compensatory Synaptic Rearrangements in Brain Circuits Controlling Memory of Presymptomatic Alzheimer's Disease Mice
(2019) In Biological Psychiatry 86(3). p.185-195- 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... (More)
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.
(Less)
- author
- Pignataro, Annabella ; Meli, Giovanni ; Pagano, Roberto ; Fontebasso, Veronica ; Battistella, Roberta LU ; Conforto, Giulia ; Ammassari-Teule, Martine and Middei, Silvia
- organization
- publishing date
- 2019
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Alzheimer disease, Amygdala, Aβ oligomers, Contextual fear conditioning, Hippocampus, Neural compensation
- in
- Biological Psychiatry
- volume
- 86
- issue
- 3
- pages
- 185 - 195
- publisher
- Elsevier
- external identifiers
-
- scopus:85057586499
- pmid:30528194
- ISSN
- 0006-3223
- DOI
- 10.1016/j.biopsych.2018.10.018
- language
- English
- LU publication?
- yes
- id
- b73d0445-66df-4508-9d3d-577e375c35ae
- date added to LUP
- 2019-01-08 13:08:34
- date last changed
- 2024-06-11 02:04:05
@article{b73d0445-66df-4508-9d3d-577e375c35ae,
abstract = {{<p>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.</p>}},
author = {{Pignataro, Annabella and Meli, Giovanni and Pagano, Roberto and Fontebasso, Veronica and Battistella, Roberta and Conforto, Giulia and Ammassari-Teule, Martine and Middei, Silvia}},
issn = {{0006-3223}},
keywords = {{Alzheimer disease; Amygdala; Aβ oligomers; Contextual fear conditioning; Hippocampus; Neural compensation}},
language = {{eng}},
number = {{3}},
pages = {{185--195}},
publisher = {{Elsevier}},
series = {{Biological Psychiatry}},
title = {{Activity-Induced Amyloid-β Oligomers Drive Compensatory Synaptic Rearrangements in Brain Circuits Controlling Memory of Presymptomatic Alzheimer's Disease Mice}},
url = {{http://dx.doi.org/10.1016/j.biopsych.2018.10.018}},
doi = {{10.1016/j.biopsych.2018.10.018}},
volume = {{86}},
year = {{2019}},
}