Canet Geoffrey, Da Gama Monteiro Felipe, Rocaboy Emma, Diego-Diaz Sofia, Khelaifia Boutheyna, Godbout Kelly, Lachhab Aymane, Kim Jessica, Valencia Daphne I, Yin Audrey, Wu Hau-Tieng, Howell Jordan, Blank Emily, Laliberté Francis, Fortin Nadia, Boscher Emmanuelle, Fereydouni-Forouzandeh Parissa, Champagne Stéphanie, Guisle Isabelle, Hébert Sébastien S, Pernet Vincent, Liu Haiyan, Lu William, Debure Ludovic, Rapoport David M, Ayappa Indu, Varga Andrew W, Parekh Ankit, Osorio Ricardo S, Lacroix Steve, Burns Mark P, Lucey Brendan P, Blessing Esther M, Planel Emmanuel
Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, Québec City, Canada.
Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, Québec City, Canada.
J Clin Invest. 2025 Feb 4;135(7):e182931. doi: 10.1172/JCI182931.
Sleep disturbance is bidirectionally associated with an increased risk of Alzheimer's disease and other tauopathies. While the sleep-wake cycle regulates interstitial and cerebrospinal fluid (CSF) tau levels, the underlying mechanisms remain unknown. Understanding these mechanisms is crucial, given the evidence that tau pathology spreads through neuron-to-neuron transfer, involving the secretion and internalization of pathological tau forms. Here, we combined in vitro, in vivo, and clinical methods to reveal a pathway by which changes in body temperature (BT) over the sleep-wake cycle modulate extracellular tau levels. In mice, a higher BT during wakefulness and sleep deprivation increased CSF and plasma tau levels, while also upregulating unconventional protein secretion pathway I (UPS-I) events including (a) intracellular tau dephosphorylation, (b) caspase 3-mediated cleavage of tau (TauC3), and (c) membrane translocation of tau through binding to phosphatidylinositol 4,5-bisphosphate (PIP2) and syndecan 3. In humans, the increase in CSF and plasma tau levels observed after wakefulness correlated with BT increases during wakefulness. By demonstrating that sleep-wake variation in BT regulates extracellular tau levels, our findings highlight the importance of thermoregulation in linking sleep disturbances to tau-mediated neurodegeneration and the preventative potential of thermal interventions.
睡眠障碍与阿尔茨海默病及其他tau蛋白病风险增加呈双向关联。虽然睡眠-觉醒周期调节间质液和脑脊液（CSF）中的tau蛋白水平，但其潜在机制仍不清楚。鉴于有证据表明tau蛋白病理通过神经元间传递传播，涉及病理性tau蛋白形式的分泌和内化，了解这些机制至关重要。在这里，我们结合体外、体内和临床方法，揭示了睡眠-觉醒周期中体温（BT）变化调节细胞外tau蛋白水平的途径。在小鼠中，清醒和睡眠剥夺期间较高的体温会增加脑脊液和血浆中的tau蛋白水平，同时还会上调非常规蛋白质分泌途径I（UPS-I）相关事件，包括（a）细胞内tau蛋白去磷酸化、（b）半胱天冬酶3介导的tau蛋白切割（TauC3）以及（c）tau蛋白通过与磷脂酰肌醇4,5-二磷酸（PIP2）和 syndecan 3结合实现膜转位。在人类中，清醒后观察到的脑脊液和血浆中tau蛋白水平升高与清醒期间的体温升高相关。通过证明体温的睡眠-觉醒变化调节细胞外tau蛋白水平，我们的研究结果突出了体温调节在将睡眠障碍与tau蛋白介导的神经退行性变联系起来方面的重要性，以及热干预的预防潜力。
