Canet, GeoffreyGeoffreyCanetDa Gama Monteiro, FelipeFelipeDa Gama MonteiroRocaboy, EmmaEmmaRocaboyDiego-Diaz, SofiaSofiaDiego-DiazKhelaifia, BoutheynaBoutheynaKhelaifiaGodbout, KellyKellyGodboutLachhab, AymaneAymaneLachhabKim, JessicaJessicaKimValencia, Daphne IDaphne IValenciaYin, AudreyAudreyYinWu, Hau-TiengHau-TiengWuHowell, Jordan CJordan CHowellBlank, EmilyEmilyBlankLaliberté, FrancisFrancisLalibertéFortin, NadiaNadiaFortinBoscher, EmmanuelleEmmanuelleBoscherFereydouni-Forouzandeh, ParissaParissaFereydouni-ForouzandehChampagne, StéphanieStéphanieChampagneGuisle, IsabelleIsabelleGuisleHébert, Sébastien SSébastien SHébertPernet, VincentVincentPernetLiu, HaiyanHaiyanLiuLu, WilliamWilliamLuDebure, LudovicLudovicDebureRapoport, David MDavid MRapoportAyappa, InduInduAyappaVarga, Andrew WAndrew WVargaParekh, AnkitAnkitParekhOsorio, Ricardo SRicardo SOsorioLacroix, SteveSteveLacroixBurns, Mark PMark PBurnsLucey, Brendan PBrendan PLuceyBlessing, Esther MEsther MBlessingPlanel, EmmanuelEmmanuelPlanel2025-03-112025-03-112025-02https://boris-portal.unibe.ch/handle/20.500.12422/204691Sleep disturbance is bidirectionally associated with increased risks 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 evidence indicates that tau pathology spreads through neuron-to-neuron transfer, involving the secretion and internalization of pathological tau forms. Here, we combine 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, higher BT during wakefulness and sleep-deprivation increased CSF and plasma tau levels, while also upregulating unconventional protein secretion pathway-I (UPS-I) components, including (i) intracellular tau dephosphorylation, (ii) caspase-3-mediated cleavage of tau (TauC3) and (iii) its membrane translocation through binding to PIP2 and syndecan-3. In humans, the increase in CSF and plasma tau levels observed post-wakefulness correlated with BT increase 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.enAlzheimer diseaseCell biologyNeuroscienceProteoglycans600 - Technology::610 - Medicine & healtharticle10.48620/858513990353010.1172/JCI182931