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<p>Sleep disturbances are associated with the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and primary tauopathies. Here we demonstrate that administration of the dual orexin receptor antagonist lemborexant in the P301S/E4 mouse model of tauopathy improves tau-associated impairments in sleep–wake behavior. It also protects against chronic reactive microgliosis and brain atrophy in male P301S/E4 mice by preventing abnormal phosphorylation of tau. These neuroprotective effects in males were not observed after administration of the nonorexinergic drug zolpidem that similarly promoted nonrapid eye movement sleep. Furthermore, both genetic ablation of orexin receptor 2 and lemborexant treatment reduced wakefulness and decreased seeding and spreading of phosphorylated tau in the brain of wild-type mice. These findings raise the therapeutic potential of targeting sleep by orexin receptor antagonism to prevent abnormal tau phosphorylation and limit tau-induced damage.</p>

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Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy

  • 期刊论文

  • 发表日期：

    2025年5月27日

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  • Samira Parhizkar,
  • Xin Bao,
  • Wei Chen,
  • Nicholas Rensing,
  • Yun Chen,
  • Michal Kipnis,
  • Sihui Song,
  • Grace Gent,
  • Eric Tycksen,
  • Melissa Manis,
  • Choonghee Lee,
  • Javier Remolina Serrano,
  • Megan E. Bosch,
  • Emily Franke,
  • Carla M. Yuede,
  • Eric C. Landsness,
  • Michael Wong,
  • David M. Holtzman

摘要

Sleep disturbances are associated with the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and primary tauopathies. Here we demonstrate that administration of the dual orexin receptor antagonist lemborexant in the P301S/E4 mouse model of tauopathy improves tau-associated impairments in sleep–wake behavior. It also protects against chronic reactive microgliosis and brain atrophy in male P301S/E4 mice by preventing abnormal phosphorylation of tau. These neuroprotective effects in males were not observed after administration of the nonorexinergic drug zolpidem that similarly promoted nonrapid eye movement sleep. Furthermore, both genetic ablation of orexin receptor 2 and lemborexant treatment reduced wakefulness and decreased seeding and spreading of phosphorylated tau in the brain of wild-type mice. These findings raise the therapeutic potential of targeting sleep by orexin receptor antagonism to prevent abnormal tau phosphorylation and limit tau-induced damage.