PDF(Pubmed)
Abstract：
Pathological proteins including tau are produced in neurons and released into interstitial fluid (ISF) in a neural activity-dependent manner during wakefulness. Pathological proteins in ISF can be removed from the brain via the glymphatic pathway during nighttime. Thus, in individuals with Alzheimer\'s disease (AD) that have dysregulated sleep/wake rhythm, application of orexin receptor 2 (OX2R) agonists during daytime could recover the efflux of pathological proteins to ISF and indirectly promote the glymphatic pathway by improving the quality of nighttime sleep after proper daytime arousal, resulting in increased removal of these proteins from the brain. We investigated this hypothesis using OX-201, a novel OX2R-selective agonist with a 50% effective concentration of 8.0 nM. Diurnal rhythm of tau release into hippocampal ISF correlated well with neuronal activity and wakefulness in wild-type mice. In both wild-type and human P301S tau transgenic mice, OX-201 induced wakefulness and promoted tau release into hippocampal ISF. Human P301S tau transgenic mice, tested under our conditions, showed longer wakefulness time, which differs from individuals with AD. OX-201 treatment over 2 months did not alter hippocampal tau levels. Although further studies are required, at a minimum OX2R agonists may not exacerbate tau accumulation in individuals with tauopathy, including AD.
摘要：
包括tau蛋白的病理蛋白在神经元中产生并在觉醒期间以神经活性依赖性方式释放到间质液(ISF)中。ISF中的病理蛋白可以在夜间通过淋巴途径从脑中去除。因此，在患有阿尔茨海默病（AD）的个体中，睡眠/觉醒节律失调，在白天应用食欲素受体2（OX2R）激动剂可以通过改善白天适当唤醒后的夜间睡眠质量来恢复病理蛋白向ISF的外排，并间接促进淋巴途径。导致这些蛋白质从大脑中的去除增加。我们使用OX-201（一种新型OX2R选择性激动剂，有效浓度为8.0nM的50％）研究了这一假设。野生型小鼠海马ISF中tau释放的昼夜节律与神经元活动和觉醒度密切相关。在野生型和人P301Stau转基因小鼠中，OX-201诱导觉醒并促进海马ISF中的tau释放。人P301Stau转基因小鼠,在我们的条件下测试，显示更长的清醒时间，这与AD的个体不同。OX-201治疗超过2个月没有改变海马tau水平。虽然还需要进一步的研究，在最低限度的OX2R激动剂可能不会加剧tau病变个体的tau积累，包括AD。
