Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau
Geoffrey Canet, … , Esther M. Blessing, Emmanuel Planel
Geoffrey Canet, … , Esther M. Blessing, Emmanuel Planel
Published February 4, 2025
Citation Information: J Clin Invest. 2025;135(7):e182931. https://doi.org/10.1172/JCI182931.
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Research Article Cell biology Neuroscience

Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau

Abstract

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.

Authors

Geoffrey Canet, Felipe Da Gama Monteiro, Emma Rocaboy, Sofia Diego-Diaz, Boutheyna Khelaifia, Kelly Godbout, Aymane Lachhab, Jessica Kim, Daphne I. Valencia, Audrey Yin, Hau-Tieng Wu, Jordan Howell, Emily Blank, Francis Laliberté, Nadia Fortin, Emmanuelle Boscher, Parissa Fereydouni-Forouzandeh, Stéphanie Champagne, Isabelle Guisle, Sébastien S. Hébert, Vincent Pernet, Haiyan Liu, William Lu, Ludovic Debure, David M. Rapoport, Indu Ayappa, Andrew W. Varga, Ankit Parekh, Ricardo S. Osorio, Steve Lacroix, Mark P. Burns, Brendan P. Lucey, Esther M. Blessing, Emmanuel Planel

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Figure 4

Wakefulness temperatures promote TauC3 secretion though its interaction with PIP2 and SDC3.

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Wakefulness temperatures promote TauC3 secretion though its interaction ...
(A and B) SDC3 knockdown decreased total tau (Tau3R) and TauC3 extracellular levels in SH-Tau3R cells exposed to 37°C, and the cotransfection of caspase 3 siRNA and SDC3 siRNA induced additive effects in the suppression of tau secretion (n = 5–6; Tukey’s test; mean ± SEM). †P < 0.05 and ††P < 0.01 versus the indicated condition. (C) EXT1 knockdown decreased total tau (Tau3R) and TauC3 extracellular levels in SH-Tau3R cells exposed to 37°C (n = 11; unpaired, 2-tailed t test; mean ± SEM). (D) Knockdown of caspase 3 and SDC3 decreased the intracellular expression of TauC, while increasing tau phosphorylation at S422 (representative Western blot; n = 3). (E) The increase in membrane fluidity was temperature dependent in SH-Tau3R cells (n = 8; Tukey’s test; box and whiskers show minimum to maximum and median). (F and G) PIP2 showed a better binding affinity for TauC3 than for full-length tau (anti-DA9, anti-Tau46, and anti-TauC antibodies) in SH-Tau3R cells exposed to 37°C. (H–J) The increase in binding between PIP2 and TauC3 was temperature dependent (n = 3; Kruskal-Wallis test; mean ± SEM). Data are from a minimum of 2 independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001 versus the respective control condition.