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Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease

Shah, D; Gsell, W; Wahis, J; Luckett, ES; Jamoulle, T; Vermaercke, B; Preman, P; ... De Strooper, B; + view all (2022) Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease. Cell Reports , 40 (8) , Article 111280. 10.1016/j.celrep.2022.111280. Green open access

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Abstract

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.

Type: Article
Title: Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.celrep.2022.111280
Publisher version: https://doi.org/10.1016/j.celrep.2022.111280
Language: English
Additional information: © 2022 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Keywords: App mice, BOLD rsfMRI, CP: Neuroscience, amyloid pathology, astrocytes, calcium signaling, neuronal hyperactivity, Alzheimer Disease, Amyloid beta-Peptides, Animals, Astrocytes, Calcium, Calcium Signaling, Disease Models, Animal, Humans, Mice, Mice, Transgenic, Neurons
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UK Dementia Research Institute HQ
URI: https://discovery.ucl.ac.uk/id/eprint/10155083
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