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 5

Wakefulness, SD, and mild hyperthermia promote UPS-I–dependent tau release in CSF in mice.

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Wakefulness, SD, and mild hyperthermia promote UPS-I–dependent tau relea...
(A) C57BL6 mice were euthanized during sleep (CT4, 10:00 am) or the active period (CT16, 8:45 pm). (B) Awake mice had higher rectal temperatures (°C) compared with sleeping mice (n = 7; unpaired, 2-tailed t test; box and whiskers with minimum to maximum and median). (C and D) Caspase 3, TauC3, SDC3, and PIP2 expression levels were increased in the cortices of awake mice compared with levels in sleeping mice, whereas p-Tau (S422) levels were decreased (n = 10; unpaired, 2-tailed t test; mean ± SEM). (E) C57BL6 mice were sleep deprived (n = 9) for 6 hours and then compared with naive mice (n = 7). (F) SD inhibited the drop in BT (°C) induced by sleep (n = 5; Tukey’s; mean ± SEM shown as error envelopes). (G and H) Caspase 3, TauC3, and PIP2 expression levels were increased in the cortices of sleep-deprived mice compared with naive mice, whereas p-Tau (S422) and Tau46 levels were decreased (unpaired, 2-tailed t test; mean ± SEM). (I and J) hTau mice were exposed for 4 hours to 4°C (hypo, n = 6) or 38°C (hyper, n = 6) and then compared with naive (normo) mice (normo, n = 5; Šidák’s test; mean ± SEM shown as error envelopes). ***P < 0.001 versus the naive (normo) group at baseline; †††P < 0.001 versus the respective group at baseline. (K) Hyperthermic (hyper) mice had higher CSF tau levels than did hypothermic (hypo) mice (n = 5 normo; n = 3 hypo; n = 6 hyper; Kruskal-Wallis test; mean ± SEM). CSF tau levels were significantly correlated with rectal BT (°C) (Pearson’s test; error envelopes are shown in gray). (L) Hyperthermic mice had higher plasma tau levels than did hypothermic mice (n = 5 normo; n = 6 hypo; n = 5 hyper; Dunnett’s test; mean ± SEM). Plasma tau levels were significantly correlated with rectal BT (°C) (Pearson’s test; error envelopes are shown in gray). Data are from a minimum of 2 independent experiments. NaN, not a number. *P < 0.05, **P < 0.01, and ***P < 0.001.