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

Disha Shah, Willy Gsell, Jérôme Wahis, Emma S. Luckett, Tarik Jamoulle, Ben Vermaercke, Pranav Preman, Daan Moechars, Véronique Hendrickx, Tom Jaspers, Kathleen Craessaerts, Katrien Horré, Leen Wolfs, Mark Fiers, Matthe Holt, Dietmar Rudolf Thal, Zsuzsanna Callaerts-Vegh, Rudi D'Hooge, Rik Vandenberghe, Uwe Himmelreich, Vincent Bonin, Bart De Strooper
Cell Reports, 2022

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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