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<p>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 <i>Adrb1</i><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, <i>Adrb1</i><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 <i>Adrb1</i><sup>A187V</sup> variant on activity and sleep regulation.</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月9日

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  • 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

摘要

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.