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Prime editing of the β1 adrenoceptor in the brain restores physiological REM sleep in a mouse model of Alzheimer’s disease

Author

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  • Desirée Böck

    (University of Zurich, Institute of Pharmacology and Toxicology
    University of Zurich and ETH Zurich, Neuroscience Center Zurich (ZNZ)
    ETH Zurich, Laboratory of Molecular and Behavioral Neuroscience, Institute for Neuroscience, Department of Health Sciences and Technology)

  • Lisa Tidecks

    (University of Zurich, Institute of Pharmacology and Toxicology)

  • Maria Wilhelm

    (University of Zurich, Institute of Pharmacology and Toxicology
    University of Zurich and ETH Zurich, Neuroscience Center Zurich (ZNZ)
    ETH Zurich, Laboratory of Molecular and Behavioral Neuroscience, Institute for Neuroscience, Department of Health Sciences and Technology)

  • Waleed ElGrawani

    (University of Zurich, Institute of Pharmacology and Toxicology
    University of Zurich and ETH Zurich, Neuroscience Center Zurich (ZNZ))

  • Sian Duss

    (University of Zurich and ETH Zurich, Neuroscience Center Zurich (ZNZ)
    ETH Zurich, Laboratory of Molecular and Behavioral Neuroscience, Institute for Neuroscience, Department of Health Sciences and Technology)

  • Chiara Trevisan

    (University of Zurich, Institute of Neuropathology)

  • Dalila Vena

    (University of Zurich, Institute of Neuropathology)

  • Anna Maria Reuss

    (University of Zurich and ETH Zurich, Neuroscience Center Zurich (ZNZ)
    University of Zurich, Institute of Neuropathology)

  • Lucas Kissling

    (University of Zurich, Institute of Pharmacology and Toxicology)

  • Matteo Ranucci

    (University of Zurich, Institute of Pharmacology and Toxicology)

  • Mattia Privitera

    (University of Zurich and ETH Zurich, Neuroscience Center Zurich (ZNZ)
    ETH Zurich, Laboratory of Molecular and Behavioral Neuroscience, Institute for Neuroscience, Department of Health Sciences and Technology)

  • Lisa K. Polzer

    (University of Zurich, Institute of Neuropathology
    Free University of Berlin, Institute of Chemistry and Biochemistry)

  • Athena E. Economides

    (University of Zurich, Institute of Neuropathology)

  • Eleonora I. Ioannidi

    (University of Zurich, Institute of Pharmacology and Toxicology)

  • Raquel Mendes

    (University of Zurich, Institute of Pharmacology and Toxicology)

  • Yanik Weber

    (University of Zurich, Institute of Pharmacology and Toxicology)

  • Justine Leonardi

    (University of Zurich and ETH Zurich, Neuroscience Center Zurich (ZNZ)
    ETH Zurich, Laboratory of Molecular and Behavioral Neuroscience, Institute for Neuroscience, Department of Health Sciences and Technology)

  • Jonas Mumenthaler

    (University of Zurich, Institute of Pharmacology and Toxicology)

  • Elina Villiger

    (University of Zurich, Institute of Pharmacology and Toxicology)

  • Romain Goutagny

    (LNCA UMR 7364, University of Strasbourg, CNRS)

  • Chantal Mathis

    (LNCA UMR 7364, University of Strasbourg, CNRS)

  • Lukas Schmidheini

    (University of Zurich, Institute of Pharmacology and Toxicology)

  • Tanja Rothgangl

    (University of Zurich, Institute of Pharmacology and Toxicology)

  • Sharan Janjuha

    (University of Zurich, Institute of Pharmacology and Toxicology)

  • Tommaso Patriarchi

    (University of Zurich, Institute of Pharmacology and Toxicology
    University of Zurich and ETH Zurich, Neuroscience Center Zurich (ZNZ))

  • Johannes Bohacek

    (University of Zurich and ETH Zurich, Neuroscience Center Zurich (ZNZ)
    ETH Zurich, Laboratory of Molecular and Behavioral Neuroscience, Institute for Neuroscience, Department of Health Sciences and Technology)

  • Yaroslav Sych

    (University of Strasbourg, Institute of Cellular and Integrative Neuroscience, CNRS UPR3212)

  • Adriano Aguzzi

    (University of Zurich and ETH Zurich, Neuroscience Center Zurich (ZNZ)
    University of Zurich, Institute of Neuropathology)

  • Jochen Winterer

    (ETH Zurich, Laboratory of Systems Neuroscience, Institute for Neuroscience, Department of Health Sciences and Technology)

  • Konstantinos Kompotis

    (University of Zurich, Institute of Pharmacology and Toxicology)

  • Gerald Schwank

    (University of Zurich, Institute of Pharmacology and Toxicology)

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 Adrb1A187V 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, Adrb1A187V 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 Adrb1A187V variant on activity and sleep regulation.

Suggested Citation

  • 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 & At, 2025. "Prime editing of the β1 adrenoceptor in the brain restores physiological REM sleep in a mouse model of Alzheimer’s disease," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65964-w
    DOI: 10.1038/s41467-025-65964-w
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