The Sleep-Wake Cycle Regulates Extracellular Tau

Post by: Amanda McFarlan

What's the science?

The aggregation of hyperphosphorylated tau protein is one of the primary markers of Alzheimer’s disease and is known to be highly correlated with neuronal and synaptic degeneration. Previous studies have shown that neurons release tau protein into the extracellular space–where it can spread from one synapse to another—and that this release is increased with elevated neuronal activity. Since the state of wakefulness, compared to sleep, is associated with increased activity, the authors hypothesized that tau may be regulated by the sleep-wake cycle. This week in Science, Holth and colleagues investigated the effect of the sleep-wake cycle on tau in rodents and humans.

How did they do it?

The authors used in vivo microdialysis to examine the effect of the sleep-wake cycle on tau and lactate (regulated by neuronal activity) levels in the brain interstitial fluid in freely behaving mice. To do this, they surgically implanted a guide cannula into the left hippocampus of wild-type mice, and after recovery, inserted a microdialysis probe to collect brain interstitial fluid samples. The levels of tau and lactate in the brain interstitial fluid were then measured in mice that underwent one of three conditions: undisturbed sleep-wake cycle (control), manual sleep deprivation, and sleep deprivation with the infusion of tetrodotoxin (reduces neuronal activity). They further tested the effect of elevated wakefulness (sleep deprivation) on interstitial fluid tau and amyloid-β levels using chemogenetic activation (DREADDs) of the brain wake circuitry. Next, the authors investigated the effect of a longer period of sleep deprivation on the ability of injected tau fibrils to seed tau pathology as well as the ability of seeded tau pathology to proliferate in the brain and promote the misfolding of other tau proteins (tau spreading). They used a transgenic mouse model of tauopathy (P301S mice) and injected recombinant human tau fibrils into the hippocampus of young male mice (not yet expressing a tau pathology). Mice underwent either 28 days of sleep deprivation using the modified multiple platform technique or a control condition. Immunohistochemistry analyses were performed to determine whether tau aggregates had spread throughout the brain. Based on their results in mice, the authors also examined the effect of the sleep deprivation on tau levels in the cerebrospinal fluid of humans. A lumbar catheter was used to collect cerebrospinal fluid in adult participants as they underwent one night of normal rest and one night of sleep deprivation. The authors also measured levels of α-synuclein (a protein associated with increased neuronal activity) as well as other neuronal and glial proteins in the cerebrospinal fluid.

What did they find?

The authors determined that tau and lactate levels in the brain interstitial fluid were higher in control mice during the period of wakefulness compared to the period of sleep. They found that sleep deprivation caused an even greater increase in tau and lactate levels in the brain interstitial fluid. In mice that were both sleep deprived and infused with tetrodotoxin (reducing neuronal activity), there were no detectable changes in tau or lactate levels in the brain interstitial fluid. They also showed that increasing wakefulness using DREADDs significantly increased tau and amyloid-β in the interstitial fluid. Together, these findings suggest that higher tau levels during wakefulness and sleep deprivation might be a result of tau secretion due to increases in neuronal metabolism and synaptic strength. Next, the authors revealed that longer periods of sleep deprivation did not alter the ability of tau fibrils to seed the misfolding of other tau proteins at the injection site, but did increase the spreading of tau pathology throughout the brain compared to control conditions. They determined that in sleep deprived animals, tau spread from the hippocampus to the locus coeruleus, a brain region involved in wakefulness, was increased. In human studies, the authors found that levels of tau and synuclein in the cerebrospinal fluid were significantly increased with a night of sleep deprivation compared to a normal night of sleep. These findings suggests that tauopathies in humans might be sensitive to the sleep-wake cycle and in particular, sleep deprivation.


What's the impact?

This is the first study to show that levels of tau in the brain interstitial fluid are modulated by the sleep-wake cycle and increased with sleep deprivation in rodents. Furthermore, the authors showed that prolonged sleep deprivation in mice significantly increases tau spreading in the brain. Similarly, sleep deprivation was shown to increase tau levels in cerebrospinal fluid in humans. Altogether, this study provides evidence for a role of sleep and wake in regulating tau and tau pathology.


Holth et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science (2019). Access the original scientific publication here.