Canet G, Da Gama Monteiro F, Rocaboy E, Diego-Diaz S, Khelaifia B, Godbout K, Lachhab A, Kim J, Valencia DI, Yin A, Wu HT, Howell JC, Blank E, Laliberté F, Fortin N, Boscher E, Fereydouni-Forouzandeh P, Champagne S, Guisle I, Hébert SS, Pernet V, Liu H, Lu W, Debure L, Rapoport DM, Ayappa I, Varga AW, Parekh A, Osorio RS, Lacroix S, Burns MP, Lucey BP, Blessing EM, Planel E. Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau. J Clin Invest. 2025 Feb 4; Epub 2025 Feb 4 PubMed.
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University of Gothenburg
In this article, Geoffrey Canet et al. provide novel insight into how sleep-wake cycles—particularly body temperature fluctuations—affect tau processing and its release into the extracellular space. The authors report that lower body temperatures increase tau phosphorylation, which inhibits its processing and prevents its release. In contrast, at higher body temperatures, dephosphorylated tau is cleaved by caspase-3, generating tau C3 fragments. These fragments bind to PIP2 at the plasma membrane and are subsequently translocated into the extracellular space via syndecan-3.
These findings align with previous research showing that soluble tau levels in human fluids (CSF and plasma) are higher after wakefulness than post-sleep (Benedict et al., 2020). The discovery that body temperature plays a key role in tau processing has significant implications for both understanding tau pathophysiology and improving its use as a biomarker for diagnosis.…More
From a mechanistic perspective, while hyperphosphorylated tau is a well-established component of neurofibrillary tangles, soluble non-phosphorylated tau—particularly the tau C3 fragment—has been identified as a key driver of tau propagation and seeding (Nicholls et al., 2017). This raises the possibility that hyperphosphorylated tau itself may not be inherently pathological. A similar phenomenon is observed in hibernating animals, such as bears and hamsters, where tau becomes hyperphosphorylated at lower temperatures during hibernation but reverses upon awakening (Dec 2022 conference news).
Given the dynamic balance between phosphorylated and non-phosphorylated tau across sleep-wake cycles, an important question arises: How do these cycles influence pathological tau aggregation and spreading? Could prolonged wakefulness exacerbate the risk of tau propagation? Conversely, could exposure to lower temperatures help mitigate it?
From a diagnostic perspective, these findings have crucial implications. Previous studies have demonstrated that tau levels, along with other biomarkers, fluctuate throughout the day, with higher levels observed in the evening compared to the morning (Orduña Dolado et al., 2024). Accounting for these variations is essential for accurately determining pathological tau levels in CSF and blood and timepoint for sample collection. Implementing dual cutoff points, as recently proposed, could help adjust for these fluctuations and improve diagnostic accuracy (Brum et al., 2023).
References:
Benedict C, Blennow K, Zetterberg H, Cedernaes J. Effects of acute sleep loss on diurnal plasma dynamics of CNS health biomarkers in young men. Neurology. 2020 Mar 17;94(11):e1181-e1189. Epub 2020 Jan 8 PubMed.
Nicholls SB, DeVos SL, Commins C, Nobuhara C, Bennett RE, Corjuc DL, Maury E, Eftekharzadeh B, Akingbade O, Fan Z, Roe AD, Takeda S, Wegmann S, Hyman BT. Characterization of TauC3 antibody and demonstration of its potential to block tau propagation. PLoS One. 2017;12(5):e0177914. Epub 2017 May 22 PubMed.
Orduña Dolado A, Stomrud E, Ashton NJ, Nilsson J, Quijano-Rubio C, Jethwa A, Brum WS, Brinkmalm Westman A, Zetterberg H, Blennow K, Janelidze S, Hansson O. Effects of time of the day at sampling on CSF and plasma levels of Alzheimer' disease biomarkers. Alzheimers Res Ther. 2024 Jun 22;16(1):132. PubMed.
Brum WS, Cullen NC, Janelidze S, Ashton NJ, Zimmer ER, Therriault J, Benedet AL, Rahmouni N, Tissot C, Stevenson J, Servaes S, Triana-Baltzer G, Kolb HC, Palmqvist S, Stomrud E, Rosa-Neto P, Blennow K, Hansson O. A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases. Nat Aging. 2023 Sep;3(9):1079-1090. Epub 2023 Aug 31 PubMed.
The University of Queensland
The study in SH-SY5Y cells, neuronal cultures, mice, and human samples by Geoffrey Canet, Emmanuel Planel, and colleagues offers interesting avenues and insight into how the sleep-wake cycle in body temperature regulates tau secretion, and their correlation with CSF and plasma tau levels. This new work emphasizes the importance of thermoregulation in neurodegeneration, given that sleep problems are a harbinger of tau-linked neurodegeneration and dementia.
Let’s also consider that mitochondria have a role in the sleep-wake cycle. Vast temperature gradients have been reported for mitochondria, which can be up to 10 degrees warmer, or better: hotter than the rest of the cell. This is still a conundrum (see Macherel et al., 2021). Given this, a follow-up question that could be addressed would be how a core body temperature variation during the sleep-wake cycle—cited in the Canet study as 3 degrees in mice and of 1.5 degrees in humans—is mirrored at a subcellular level, say in mitochondria, and how this relates to tau secretion.…More
It would also be worth in a follow-up taking these new findings to hibernating animals, since nine years ago Thomas Arendt and colleagues reported that reversible hyperphosphorylation of tau occurs under physiologically controlled conditions during hibernation (Bullmann et al., 2016).
In relation to this new study in JCI, I would find it worth assessing phosphorylation sites other than S422, which could be done by an unbiased phospho-proteomic approach, and whether exosome-mediated tau release is also affected by core body temperature variation.
References:
Macherel D, Haraux F, Guillou H, Bourgeois O. The conundrum of hot mitochondria. Biochim Biophys Acta Bioenerg. 2021 Feb 1;1862(2):148348. Epub 2020 Nov 26 PubMed.
Bullmann T, Seeger G, Stieler J, Hanics J, Reimann K, Kretzschmann TP, Hilbrich I, Holzer M, Alpár A, Arendt T. Tau phosphorylation-associated spine regression does not impair hippocampal-dependent memory in hibernating golden hamsters. Hippocampus. 2016 Mar;26(3):301-18. Epub 2015 Oct 13 PubMed.
University of California, Irvine
Canet et al. outline new in vitro and in vivo evidence from across species that supports a role for fluctuations in core body temperature in the production and secretion of tau pathology. They first demonstrate in cells that manipulating external temperatures can upregulate a core biological pathway, the unconventional protein secretion pathway-I , which is known to promote tau secretion. They then show in mice and in humans that during waking periods, and following sleep deprivation, tau increases in correlation with wake-associated body temperature changes. Though the mechanisms linking sleep and circadian disturbance to increased dementia risk are not fully worked out, this work offers a potentially novel mechanism that could support new therapeutic targets.…More
While it remains to be seen if body temperature associations with tau are independent of, or primarily driven by, neurometabolic changes associated with wake-related increases in neuronal activity, these findings do point to a physiological signal that is readily measurable in humans using non-invasive methods. This could have important implications for how we think about relationships between dementia risk and sleep and circadian disturbances.
Further, core body temperature does fluctuate more in individuals who have fragmented sleep, insomnia disorder, or disrupted circadian rhythms, all of which associate with increased dementia risk. Follow-up work examining if regulating circadian patterns of core body temperature, or reducing core body temperature during sleep, will impact tau secretion, neurofibrillary tangle burden and spread, and dementia risk is needed to verify the clinical significance of this work.
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