Activity-Induced Amyloid-ß Oligomers Drive Compensatory Synaptic Rearrangements in Brain Circuits Controlling Memory of Presymptomatic Alzheimer's Disease Mice.
Biol Psychiatry
; 86(3): 185-195, 2019 08 01.
Article
em En
| MEDLINE
| ID: mdl-30528194
ABSTRACT
BACKGROUND:
A consistent proportion of individuals at risk for Alzheimer's disease show intact cognition regardless of the extensive accumulation of amyloid-ß (Aß) peptide in their brain. Several pieces of evidence indicate that overactivation of brain regions negative for Aß can compensate for the underactivation of Aß-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 Aß accumulation. A molecular biology approach combined with intrahippocampal injection of a γ-secretase inhibitor evaluates the impact of Aß fluctuations on spine rearrangements.RESULTS:
Encoding of CFC increases Aß oligomerization in the hippocampus but not in the amygdala of Tg2576 mice. The presence of Aß 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 Aß 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 Aß load. Furthermore, it unravels an activity-mediated feedback loop through which neuronal activation during CFC encoding favors Aß oligomerization in the hippocampus and prevents synaptic rearrangements in this region.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
1_ASSA2030
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
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Espinhas Dendríticas
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Medo
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Doença de Alzheimer
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Memória
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Vias Neurais
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Biol Psychiatry
Ano de publicação:
2019
Tipo de documento:
Article