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 $^{A187V}$ 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.
Authors
- Jonas Mumenthaler (ORCID: https://orcid.org/0000-0002-4239-9780)
- Romain Goutagny (ORCID: https://orcid.org/0000-0002-1268-533X)
- Sian N. Duss (ORCID: https://orcid.org/0000-0003-0212-0324)
- Maria Wilhelm
- Lukas Schmidheini (ORCID: https://orcid.org/0000-0001-5993-9985)
- 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)
- Konstantinos Kompotis (ORCID: https://orcid.org/0000-0003-4106-4062)
- Athena Economides
- 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)
- Lisa Tidecks (ORCID: https://orcid.org/0009-0006-9535-9586)
- Lisa Polzer
- Waleed ElGrawani (ORCID: https://orcid.org/0009-0001-5071-1500)
- Dalila Laura Vena (ORCID: https://orcid.org/0009-0007-6863-7349)
- Elina Andrea Villiger
- Chantal Mathis (ORCID: https://orcid.org/0000-0002-6663-5282)
- Desirée Böck
- Johannes Bohacek
- Justine Leonardi
- et. al.
- Adriano Aguzzi
- Matteo Ranucci
- Eleonora I. Ioannidi
- Raquel Mendes
Publication Details
- Journal
- Universität Zürich, ZORA
- Published
- 2025-12-09
- DOI
- https://doi.org/10.5167/uzh-292435
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 0.00