Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer’s disease
Authors listDisha Shah Willy Gsell Jérôme Wahis Emma S Luckett Tarik Jamoulle Ben Vermaercke Pranav Preman Daan Moechars Véronique Hendrickx Tom Jaspers Katleen Craessaerts Katrien Horré Leen Wolfs Mark Fiers Matthew Holt Dietmar Rudolf Thal Zsuzsanna Callaerts-Vegh Rudi D’Hooge Rik Vandenberghe Uwe Himmelreich Vincent Bonin Bart De Strooper
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 App 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.