Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau
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
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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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 1

Tau secretion is temperature dependent in neuronal cells.

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Tau secretion is temperature dependent in neuronal cells. (A) Twenty-fou...
(A) Twenty-four hours after seeding, SH-Tau3R cells were exposed to 35°C, 37°C, 38°C, or 39°C for 72 hours. (B) Extracellular accumulation of tau protein (Tau3R) (n = 6–12; mean ± SEM; error envelopes are shown in light purple) and LDH (n = 4–9; mean ± SEM) over time in cell medium of neurons cultured at 37°C. (C) The increase in extracellular tau levels (pg/mL) was temperature dependent in SH-Tau3R cells exposed to 35°C, 37°C, or 38°C for 72 hours (n = 6; Tukey’s test; box and whiskers show minimum to maximum and median). (D and E) The increase in extracellular tau levels was temperature dependent (Tau3R, TauC, DA9, and Tau12 antibodies) in SH-Tau3R cells exposed to 35°C, 37°C, or 38°C (n = 7–16; Tukey’s test; mean ± SEM). (F and G) The phosphorylation level of extracellular tau at AT270 (T181), S199, CP13 (S202), T205, AT100 (S212/S214), MC6 (S235), and PHF1 (S396/S404) was decreased at 38°C compared with 35°C or 37°C (n = 7–16; Tukey’s test; mean ± SEM. (H) Four days after seeding, mouse primary cortical neurons were exposed at 35°C, 37°C, or 38°C for 72 hours. (I) The increase in extracellular tau levels was temperature dependent in mouse primary neurons exposed to 35°C, 37°C, or 38°C (n = 6; Dunnett’s test; box and whiskers show minimum to maximum and median). (J and K) The increase in extracellular tau levels was temperature dependent (Tau3R antibody), whereas its phosphorylation level at S199 and T205 was decreased at 38°C compared with 35°C or 37°C (n = 11–12; Tukey’s test; mean ± SEM). (K) Data are from a minimum of 2 independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001.