Another Reason to Catch Some Zzzs: Sleep Regulates Tau Release

As if we needed yet another reason to get a good night’s sleep. David Holtzman and colleagues at Washington University in St. Louis claim in the January 24 Science that tau in a person’s cerebrospinal fluid tapers off during sleep and spikes when awake or sleep-deprived. They report the same for mouse interstitial fluid—and just like with Aβ, tau release from neurons depended on excitatory neuronal activity, and sleep deprivation hastened the spread of tau aggregates in mice. “The data suggest that wakefulness regulates normal and probably pathologic tau release. We need to better understand the process that allows tau to get out of cells, and how that might affect tauopathies,” Holtzman told Alzforum.

  • In mice, extracellular tau levels double during wakefulness.
  • In people, CSF tau rises by 50 percent after sleep deprivation.
  • Sleep deprivation in tauopathy mice hastens the spread of tangles.

Other researchers expressed surprise that tau followed a daily rhythm in mice, because the protein has a long half-life and was believed to change only sluggishly. “It's fascinating that the sleep/wake cycle regulates tau release,” Amy Pooler at the Nestlé Institute of Health Sciences in Lausanne, Switzerland, wrote to Alzforum. Bryce Mander at the University of California, Irvine, urged further research. “We now know that sleep is related to both Aβ and tau, but we don’t know the underlying mechanisms, their temporal dynamics over decades, the causal directionality of those relationships, or whether sleep-based treatment interventions can slow the buildup and spread of AD pathology,” he wrote.

Holtzman and colleagues previously reported that synaptic activity stimulated soluble Aβ release into the interstitial fluid of wild-type mouse brains (Dec 2005 news). ISF Aβ levels were tied to sleep, peaking in waking animals. In addition, sleep deprivation sped up plaque formation in AD mouse models (Sep 2009 news). At first, it seemed unlikely to Holtzman that tau would follow a similar pattern, because it is primarily a cytosolic rather than a secreted protein. However, tau also congregates in the synapse, and both Holtzman and Pooler recently reported that excitatory neuronal activity stimulates its release (Pooler et al., 2013; Feb 2014 news). 

Accelerating Tauopathy. In a tauopathy mouse model, tangles (black) invade the locus coeruleus faster when animals are sleep-deprived (right) than in controls (left). [Courtesy of Holth et al., Science/AAAS.]

In the current study, joint first authors Jerrah Holth and Sarah Fritschi found that ISF tau doubled when mice were awake. They saw the same rise when they kept mice awake during their normal sleep period. Tau levels correlated with neuronal activity, and silencing hippocampal neurons with tetrodotoxin during sleep deprivation prevented the surge. Conversely, stimulating only excitatory neurons in the supramammillary nucleus, a brain region that controls waking, kept mice awake and bumped up ISF tau.

Would the pattern hold in people? The authors analyzed CSF samples collected during a previous stable isotope labeling kinetics (SILK) sleep study, comparing tau levels in six volunteers after a good night’s sleep to levels after staying up all night (Jan 2018 news). Sleep deprivation caused tau to rise by 50 percent, outpacing the 30 percent bump in Aβ42. α-Synuclein rose in tandem with tau, as did lactate, a marker of metabolic stress. However, levels of primarily intracellular proteins such as GFAP and NfL did not budge. “The data suggest the effect is specific to certain proteins. I think the differences we see are due to altered release of tau, rather than altered clearance,” Holtzman said.

Henrik Zetterberg at the University of Gothenburg, Sweden, suggested that because CSF tau levels appeared to rise throughout the day, researchers should consider standardizing CSF sampling time, perhaps to a period between 9 a.m. and noon. Sigrid Veasey at the University of Pennsylvania, Philadelphia, noted that tau levels appeared to vary much more between individuals after sleep deprivation than under normal conditions, hinting that some people may be more susceptible to the effects of lost sleep. “Are those people more predisposed to developing a tauopathy?” she wondered.

Holtzman and colleagues also wondered if lack of sleep might promote pathology. To examine this, they injected tau fibrils into the hippocampi of eight-week-old P301S mice. Sixteen were allowed to live on as normal, while another 16 were kept awake for the next 28 days. In these sleep-deprived mice, tau tangles spread faster than in controls, covering twice as much area in the locus coeruleus (LC, see image above).

“That sleep deprivation enhances tau spread is really eye-opening, and probably the most significant aspect of this paper,” Mander said. Veasey was intrigued that the pattern of progression seemed to preferentially hit the LC, noting that its neurons are particularly affected by sleep loss. Veasey has similar findings in this P301S mouse strain, recently reporting that chronic sleep shortage hastens tau phosphorylation, tangle formation, neurodegeneration, and the emergence of motor deficits (Zhu et al., 2018; Dec 2017 conference news). Marc Diamond, University of Texas Southwestern Medical Center in Dallas, wondered whether sleep deprivation increases the secretion of tau species that corrupt folding of normal tau, as opposed to secretion of just monomers.

Other findings link tau pathology to poor sleep quality (Jan 2019 news). Holtzman thinks there may be a vicious cycle. “If you have sleep disruption, that may accelerate the development of tau pathology, and once you get tau pathology, that causes problems with sleep,” he speculated.

Perhaps reassuringly, Zetterberg’s research suggests that only complete sleep deprivation budges CSF biomarkers. He found no change in Aβ and tau biomarkers in volunteers who slept four hours per day for five nights in a row (Olsson et al., 2018). Zetterberg noted that these volunteers still obtained a normal amount of deep, slow-wave sleep each night. This type of sleep is thought to be the most protective for the brain. “One or a few nights of short sleep does not affect tau concentration,” he concluded.

Holtzman plans to investigate whether enhancing slow-wave sleep in mice slows the progression of tau pathology. This type of intervention might be possible in people too; new research reports that rocking during sleep lengthens slow-wave slumber in healthy adults (Jan 2019 news).—Madolyn Bowman Rogers

Comments

  1. This fantastic collection of studies reveals several points worth emphasizing. The group finds tau (and to lesser extents Aβ and α-synuclein) responses to sleep loss to parallel lactate changes, while other proteins respond differently. This suggests that a mechanism beyond interstitial fluid clearance governs levels across sleep-wake. These proteins and peptides, which intriguingly tend to aggregate in neurodegenerative processes, increase not only with neuronal activity but metabolic challenge, presumably from sustained increased activity (as evidenced by the increased lactate).

    This metabolic challenge component of sleep loss may also contribute to the interesting pattern of tau spread that the group finds from the hippocampus all the way back to the locus coeruleus, a group of neurons particularly metabolically challenged by sleep loss. The hippocampus is highly connected and tau could have spread in numerous regions and even locally. Instead, it spreads to the rare neuron in the locus coeruleus and entorhinal cortex. These are areas where we have shown evidence of metabolic challenges caused by chronic sleep loss, including increased levels of oxidized tau and tau oligomers.

    Perhaps the most tantalizing point is that in rested conditions human tau shows little variance among participants, but in response to sleep loss the error bars expand, suggesting tau increases far more in some humans acutely in response to sleep loss than others. Are those humans more predisposed to developing a tauopathy, including Alzheimer’s? Only time will tell.

    View all comments by Sigrid Veasey

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References

News Citations

  1. Paper Alert: Synaptic Activity Increases Aβ Release
  2. Sleep Deprivation Taxes Neurons, Racks Up Brain Aβ?
  3. Neurons Release Tau in Response to Excitation
  4. Skimping on Sleep Makes For More Aβ in the Brain
  5. Disturbed Sleep Exerts Toll on Memory and Neurodegeneration
  6. Tau, More than Aβ, Affects Sleep Early in Alzheimer’s
  7. Rocking Improves Sleep and Memory in Adults

Research Models Citations

  1. Tau P301S (Line PS19)

Paper Citations

  1. Pooler AM, Phillips EC, Lau DH, Noble W, Hanger DP. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 2013 Apr;14(4):389-94. PubMed.
  2. Zhu Y, Zhan G, Fenik P, Brandes M, Bell P, Francois N, Shulman K, Veasey S. Chronic Sleep Disruption Advances the Temporal Progression of Tauopathy in P301S Mutant Mice. J Neurosci. 2018 Nov 28;38(48):10255-10270. Epub 2018 Oct 15 PubMed.
  3. Olsson M, Ärlig J, Hedner J, Blennow K, Zetterberg H. Sleep deprivation and cerebrospinal fluid biomarkers for Alzheimer's disease. Sleep. 2018 May 1;41(5) PubMed.

Further Reading

Primary Papers

  1. Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019 Feb 22;363(6429):880-884. Epub 2019 Jan 24 PubMed.

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