Journal
CELL REPORTS
Volume 40, Issue 8, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.111280
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Funding
- Fund for Scientific Research Flanders (FWO)
- FWO Kre-diet aan Navorsers
- Alzheimer's Association(Alzheimer's Association Research Fellowship) [12R1122N]
- European Molecular Biology Organization [1502020N]
- FWO [2019-AARF-640959]
- Krediet aan Navorsers [7806]
- European Research Council (ERC) [12V7519N, 12V7522N, 1513020N, CELLPHASE_AD834682]
- KU Leuven [G0F8516N]
- VIB [G065721N]
- Stichting Alz-heimer Onderzoek Belgium (SAO)
- Elisabeth Foundation
- KU Leuven
- Flemish Government
- Dementia Research Institute -MRC (United Kingdom)
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The dysfunctions of network activity and functional connectivity are early events in Alzheimer's disease (AD), and the underlying mechanisms involve decreased astrocyte calcium signaling. This study demonstrates the role of astrocytes in mediating the initial features of AD and driving clinically relevant phenotypes.
Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer's disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.
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