Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau
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
- Emmanuel Planel (ORCID: https://orcid.org/0000-0001-5128-0565)
- Steve Lacroix (ORCID: https://orcid.org/0000-0003-0781-6371)
- Emmanuelle Boscher
- Geoffrey Canet (ORCID: https://orcid.org/0000-0001-7291-4512)
- Vincent Pernet (ORCID: https://orcid.org/0000-0002-9618-972X)
- Ricardo S. Osorio (ORCID: https://orcid.org/0000-0002-2735-9609)
- Nadia Fortin
- Esther Blessing (ORCID: https://orcid.org/0000-0002-7961-8844)
- Jessica Kim (ORCID: https://orcid.org/0000-0002-2965-226X)
- Hau‐Tieng Wu (ORCID: https://orcid.org/0000-0002-0253-3156)
- Brendan P. Lucey (ORCID: https://orcid.org/0000-0001-5400-825X)
- Parissa Fereydouni-Forouzandeh (ORCID: https://orcid.org/0000-0002-7839-0876)
- Indu Ayappa (ORCID: https://orcid.org/0000-0001-8027-9467)
- Andrew W. Varga (ORCID: https://orcid.org/0000-0002-3668-3371)
- Sébastien S. Hébert (ORCID: https://orcid.org/0000-0002-0391-9325)
- Ankit Parekh (ORCID: https://orcid.org/0000-0002-5396-0553)
- David M. Rapoport (ORCID: https://orcid.org/0000-0002-4855-2600)
- Isabelle Guisle (ORCID: https://orcid.org/0000-0001-8726-4946)
- Ludovic Debure
- Mark P. Burns (ORCID: https://orcid.org/0000-0003-4750-2000)
- Emma Rocaboy
- Sofia Diego-Diàz
- Boutheyna Khelaifia
- Haiyan Liu (ORCID: https://orcid.org/0000-0002-3154-8285)
- A. Yin (ORCID: https://orcid.org/0000-0002-1313-9314)
- William Lu
- Francis Laliberté
- Felipe Da Gama Monteiro
- Daphne Valencia
- Jordan Howell
- S. Champagne
- Krystelle Godbout
- Emily Blank
- Aymane Lachhab
Institutions
- University of Bern (CH)
- Georgetown University (US)
- Washington University in St. Louis (US)
- Georgetown University Medical Center (US)
- University Hospital of Bern (CH)
- Centre hospitalier de l'Université Laval (CA)
- Université Laval (CA)
- New York University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-02-04
- DOI
- https://doi.org/10.1172/jci182931
- Citations
- 4
- Primary Topic
- Sleep and Wakefulness Research
- Type
- article
- Field-Weighted Citation Impact
- 5.72
Funders
- BrightFocus Foundation
- Alzheimer Society
- National Institutes of Health
- Canadian Institutes of Health Research
- Fonds de Recherche du Québec - Santé