PDF(Pubmed)
Abstract：
The sleep-wake cycle regulates interstitial fluid and cerebrospinal fluid (CSF) tau levels in both mouse and human by mechanisms that remain unestablished. Here, we reveal a novel pathway by which wakefulness increases extracellular tau levels in mouse and humans. In mice, higher body temperature (BT) associated with wakefulness and sleep deprivation increased CSF tau. In vitro, wakefulness temperatures upregulated tau secretion via a temperature-dependent increase in activity and expression of unconventional protein secretion pathway-1 components, namely caspase-3-mediated C-terminal cleavage of tau (TauC3), and membrane expression of PIP2 and syndecan-3. In humans, the increase in both CSF and plasma tau levels observed post-wakefulness correlated with BT increase during wakefulness. Our findings suggest sleep-wake variation in BT may contribute to regulating extracellular tau levels, highlighting the importance of thermoregulation in pathways linking sleep disturbance to neurodegeneration, and the potential for thermal intervention to prevent or delay tau-mediated neurodegeneration.
摘要：
睡眠-觉醒周期通过尚未建立的机制调节小鼠和人类的间质液和脑脊液（CSF）tau水平。这里,我们揭示了一个新的途径，通过这个途径，清醒增加小鼠和人类细胞外tau水平。在老鼠身上,与清醒和睡眠剥夺相关的较高体温（BT）会增加CSFtau。体外，觉醒温度通过温度依赖性增加非常规蛋白质分泌途径-1组分的活性和表达来上调tau分泌，即caspase-3介导的tau（TauC3）的C端切割，PIP2和syndecan-3的膜表达。在人类中,觉醒后观察到的CSF和血浆tau水平的增加与觉醒期间的BT增加相关。我们的发现表明，BT的睡眠-觉醒变化可能有助于调节细胞外tau水平，强调体温调节在将睡眠障碍与神经变性联系起来的途径中的重要性，以及热干预预防或延迟tau介导的神经变性的潜力。
