美国华盛顿大学医学院David M. Holtzman团队的一项最新研究探明了Lemborexant改善tau介导的睡眠缺失和雄性小鼠tau病模型中的神经变性。2025年5月27日，国际知名学术期刊《自然—神经科学》发表了这一成果。

本研究表明，在P301S/E4小鼠模型中使用双食欲素受体拮抗剂lemborexant可改善睡眠-觉醒行为中tau相关的损伤。它还通过防止tau蛋白的异常磷酸化，对雄性P301S/E4小鼠的慢性反应性小胶质细胞增生和脑萎缩具有保护作用。在男性服用非食欲能药物唑吡坦后，没有观察到这些神经保护作用，唑吡坦同样促进了非快速眼动睡眠。

此外，食欲素受体2的基因消融和lemborexant治疗都减少了野生型小鼠的清醒，减少了磷酸化tau在大脑中的播种和扩散。这些发现提高了通过食欲素受体拮抗剂靶向睡眠的治疗潜力，以防止异常的tau磷酸化和限制tau诱导的损伤。

据悉，睡眠障碍与阿尔茨海默病和原发性tau蛋白病等神经退行性疾病的发病机制有关。

附：英文原文

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

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

Issue&Volume: 2025-05-27

Abstract: 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.

DOI: 10.1038/s41593-025-01966-7

Source: https://www.nature.com/articles/s41593-025-01966-7