Prime editing of the β1 adrenoceptor in the brain restores physiological REM sleep in a mouse model of Alzheimer’s disease
Year: 2025
Type: article
Abstract: Prime editing offers versatile genome modifications with therapeutic potential; yet its use to modulate neural circuitry remains underexplored. Here, we used adeno-associated viral vectors to deliver prime editors into the mouse brain and introduced the naturally occurring Adrb1 A187V variant of the β1-adrenergic receptor, linked to short sleep in humans and mice. Editing reached up to 28.1% in the cortex six months after intracerebroventricular injection and increased excitability of β1-noradrenergic neurons. This enhanced wake-associated behaviors, including home cage activity, locomotion, exploration, and recognition memory, while reducing slow wave activity (SWA) during non-rapid eye movement (NREM) sleep indicating reduced build-up of sleep pressure during active phases. In a mouse model of Alzheimer’s disease, Adrb1 A187V installation restored physiological REM sleep and again reduced NREM sleep SWA following spontaneous activity. Together, these findings demonstrate the feasibility of prime editing for reprogramming genetic circuits in the brain and reveal beneficial effects of the Adrb1 A187V variant on activity and sleep regulation.
Source: Nature Communications
Authors: Desirée Böck, Lisa Tidecks, Maria Wilhelm, Waleed ElGrawani, Sian Duss, Chiara Trevisan, Dalila Vena, Anna Maria Reuss, Lucas Kissling, Matteo Ranucci, Mattia Privitera, Lisa K. Polzer, Athena E. Economides, Eleonora I. Ioannidi, Raquel Mendes, Yanik Weber, Justine Leonardi, Jonas Mumenthaler, Elina Villiger, Romain Goutagny, Chantal Mathis, Lukas Schmidheini, Tanja Rothgangl, Sharan Janjuha, Tommaso Patriarchi, Johannes Bohacek, Yaroslav Sych, Adriano Aguzzi, Jochen Winterer, Konstantinos Kompotis, Gerald Schwank
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, Michael J. Fox Foundation for Parkinson's Research, Alzheimer's Association, Novartis Foundation, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Eidgenössische Technische Hochschule Zürich, Université de Strasbourg, Novartis Stiftung für Medizinisch-Biologische Forschung, Centre National de la Recherche Scientifique, Universität Zürich, Helmut Horten Stiftung, Foundation for Research in Science and the Humanities
Awards: Establishment of in vivo CRISPR-Cas base editor approaches to treat monogenetic liver diseases, Modifiers and cofactors of prion replication, toxicity and tropism, Identification of retromer modifiers by arrayed genome-wide perturbation, Towards therapeutic use of CRISPR/Cas9-mediated prime editing in the brain, G29155917, G325848743, The prion protein in health and disease, G7776669727, G7983326833, G8690818240
OpenAlex ID: W4417154667