Prime editing of the β1 adrenoceptor in the brain restores physiological REM sleep in a mouse model of Alzheimer’s disease
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<sup>A187V</sup> 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<sup>A187V</sup> 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<sup>A187V</sup> variant on activity and sleep regulation.
Authors
- Jonas Mumenthaler (ORCID: https://orcid.org/0000-0002-4239-9780)
- Romain Goutagny (ORCID: https://orcid.org/0000-0002-1268-533X)
- Gerald Schwank (ORCID: https://orcid.org/0000-0003-0767-2953)
- Sian N. Duss (ORCID: https://orcid.org/0000-0003-0212-0324)
- Adriano Aguzzi (ORCID: https://orcid.org/0000-0002-0344-6708)
- Maria Wilhelm
- Athena Economides (ORCID: https://orcid.org/0000-0003-2340-6364)
- Lukas Schmidheini (ORCID: https://orcid.org/0000-0001-5993-9985)
- Raquel Mendes (ORCID: https://orcid.org/0000-0003-3079-6647)
- Johannes Bohacek (ORCID: https://orcid.org/0000-0002-8442-653X)
- Sharan Janjuha (ORCID: https://orcid.org/0000-0002-5910-2912)
- Jochen Winterer (ORCID: https://orcid.org/0000-0002-6800-6594)
- Tanja Rothgangl (ORCID: https://orcid.org/0000-0001-7799-2413)
- Anna Maria Reuss (ORCID: https://orcid.org/0000-0003-1096-3030)
- Chiara Trevisan (ORCID: https://orcid.org/0000-0002-3997-094X)
- Tommaso Patriarchi (ORCID: https://orcid.org/0000-0001-9351-3734)
- Konstantinos Kompotis (ORCID: https://orcid.org/0000-0003-4106-4062)
- Yanik Weber (ORCID: https://orcid.org/0000-0002-0914-8541)
- Mattia Privitera (ORCID: https://orcid.org/0000-0002-5660-5901)
- Lucas Kissling (ORCID: https://orcid.org/0000-0002-4989-0695)
- Yaroslav Sych (ORCID: https://orcid.org/0000-0002-1822-8631)
- Matteo Ranucci (ORCID: https://orcid.org/0000-0003-3332-6202)
- Lisa Tidecks (ORCID: https://orcid.org/0009-0006-9535-9586)
- Waleed ElGrawani (ORCID: https://orcid.org/0009-0001-5071-1500)
- Dalila Laura Vena (ORCID: https://orcid.org/0009-0007-6863-7349)
- Elina Andrea Villiger
- Eleonora I. Ioannidi (ORCID: https://orcid.org/0009-0008-3005-2684)
- Chantal Mathis (ORCID: https://orcid.org/0000-0002-6663-5282)
- Desirée Böck
- Lisa K. Polzer (ORCID: https://orcid.org/0009-0007-5279-0883)
- Justine Leonardi (ORCID: https://orcid.org/0009-0008-3555-5563)
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Zurich (CH)
- ETH Zurich (CH)
- Institut des Neurosciences Cellulaires et Intégratives (FR)
- Université de Strasbourg (FR)
- Freie Universität Berlin (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-09
- DOI
- https://doi.org/10.1038/s41467-025-65964-w
- Primary Topic
- Neurobiology and Insect Physiology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
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