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

doi:10.1172/JCI182931

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

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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, …

The Journal of clinical investigation, Vol.135(7), e182931

15/04/2025

DOI: https://doi.org/10.1172/JCI182931

PMID: 39903530

Résumé

Aged

Alzheimer Disease - blood

Animals

Body Temperature

Caspase 3 - metabolism

Female

Humans

Male

Mice

Mice, Transgenic

Sleep - physiology

tau Proteins - blood

tau Proteins - cerebrospinal fluid

tau Proteins - metabolism

Wakefulness

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.

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Titre: Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau
Créateurs - sans rôle: Geoffrey Canet - Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, Québec City, Canada
Felipe Da Gama Monteiro - Université Laval, Faculté de Médecine, Département de Médecine Moléculaire, Québec, Québec City, Canada
Emma Rocaboy - Université Laval
Sofia Diego-Diaz - Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, Québec City, Canada
Boutheyna Khelaifia - Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, Québec City, Canada
Kelly Godbout - Université Laval
Aymane Lachhab - Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, Québec City, Canada
Jessica Kim - Department of Psychiatry, NYU Grossman School of Medicine, New York, New York, USA
Daphne I Valencia - Mount Sinai Integrative Sleep Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Audrey Yin - Department of Psychiatry, NYU Grossman School of Medicine, New York, New York, USA
Hau-Tieng Wu - Department of Psychiatry, NYU Grossman School of Medicine, New York, New York, USA
Jordan Howell - Department of Psychiatry, NYU Grossman School of Medicine, New York, New York, USA
Emily Blank - Department of Psychiatry, NYU Grossman School of Medicine, New York, New York, USA
Francis Laliberté - Centre de recherche du CHU de Québec-Université Laval
Nadia Fortin - Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, Québec City, Canada
Emmanuelle Boscher - Université Laval
Parissa Fereydouni-Forouzandeh - Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, Québec City, Canada
Stéphanie Champagne - Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, Québec City, Canada
Isabelle Guisle - Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, Québec City, Canada
Sébastien S Hébert - Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, Québec City, Canada
Vincent Pernet - Department of Biomedical Research, University of Bern, Bern, Switzerland
Haiyan Liu - Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
William Lu - Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
Ludovic Debure - Department of Psychiatry, NYU Grossman School of Medicine, New York, New York, USA
David M Rapoport - Mount Sinai Integrative Sleep Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Indu Ayappa - Mount Sinai Integrative Sleep Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Andrew W Varga - Mount Sinai Integrative Sleep Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Ankit Parekh - Mount Sinai Integrative Sleep Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Ricardo S Osorio - Department of Psychiatry, NYU Grossman School of Medicine, New York, New York, USA
Steve Lacroix - Université Laval, Faculté de Médecine, Département de Médecine Moléculaire, Québec, Québec City, Canada
Mark P Burns - Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA
Brendan P Lucey - Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
Esther M Blessing - Department of Psychiatry, NYU Grossman School of Medicine, New York, New York, USA
Emmanuel Planel - Université Laval
Détails de publication: The Journal of clinical investigation, Vol.135(7), e182931
Note de subvention: K25 HL151912 / NHLBI NIH HHS P30 AG066514 / NIA NIH HHS R01 HL171813 / NHLBI NIH HHS R01 AG070866 / NIA NIH HHS K76 AG054863 / NIA NIH HHS R21 HL165320 / NHLBI NIH HHS R21 HL173733 / NHLBI NIH HHS
Identifiants: 99162987209311
Unité académique: Institut de Génomique Fonctionnelle - IGF
Langue: English
Type de ressource: Journal article