To Sleep, Perchance to Treat Tauopathies
By Gabriela O. Escalante
It turns out that sleep, “that balm of hurt minds”, may actually help “raze out the written troubles of the brain”—to use Shakespeare’s description in Macbeth. At least, that’s what a 2019 paper published in Science [1] and its accompanying editorial [2] suggest. A group of scientists from four universities reported that a lack of sleep may enhance the deposition of Tau protein (TP) in the brain. TP is a cellular protein found in the central nervous system that helps stabilize microtubules, structures that serve as the neuron’s internal skeleton. TP may be involved in the pathogenesis of Alzheimer’s disease (AD) as well as other diseases called “tauopathies,” which include Parkinson’s disease and chronic traumatic encephalopathy that afflicts boxers and NFL players. In these diseases, aggregates of TP and beta-amyloid are deposited in the brain, forming neurofibrillary tangles.
Cognitive decline is more strongly associated with TP deposits than with beta-amyloid aggregates [1], suggesting that TP plays a more prominent pathogenic role.
Using micro-brain surgery techniques and stereotaxic equipment, researchers prodded mice with their fingers to keep them awake, while measuring the production of TP in the animals’ cerebral interstitial fluid, the watery substance between brain cells. During the procedure, mice were put under general anesthesia, but when they awoke, they were able to move around freely in their cages, eat, and sleep. The findings were dramatic: while mice were kept awake, the production of TP increased by 50%. Authors then examined the transportation of TP within the brain by injecting recombinant TP into the mice’s brain hippocampus. After 28 days of sleep deprivation they found increased spreading of TP to other brain regions connected to the hippocampus, the brain’s memory center.
Although the above experiment seems to support the hypothesis that sleeplessness raises brain TP production and transportation, there’s a rub: what if keeping mice awake by the relatively crude approach of finger-prodding may have raised brain TP by mechanisms that were unrelated to sleep deprivation? Seeking a “pure” method of inducing persistent wakefulness, the researchers embarked on a series of chemogenetic experiments. The authors used adeno-associated viruses (AAV) to stereotaxically transfect the gene for a DREADD receptor (DREADD stands for “designer receptor exclusively activated by designer drugs”) into the neurons in a part of the mouse brain’s hypothalamus that controls sleep and arousal called the supramammillary nucleus (SuM). They then gave the mice clozapine-N-oxide (CNO), a drug designed to specifically activate the DREADD receptor transfected into the SuM neurons. The mice treated in this way experienced prolonged wakefulness, during which they displayed increased TP production in brain interstitial system. Similarly, mice who were not transfected with the DREADD receptor did not experience prolonged wakefulness after administration of CNO or a placebo. These results suggest that sleep deprivation is associated with elevated TP production.
As convincing as these experiments may seem, their significance would be considerably amplified by replication of at least some of the findings in humans. Although it is highly unlikely that humans would volunteer for experiments to obtain interstitial brain fluid or submit to DREADD receptor gene transfection into the brain, authors did have access to something similar: cerebrospinal fluid (CSF) from humans who volunteered to spend three nights in a research unit while their CSF was drained through an indwelling spinal catheter. At random, the volunteers were either kept awake by the nursing staff for 36 hours or allowed to sleep. Similar to the mouse model, TP concentration in the CSF increased by more than 50% while the volunteers were kept awake.
The above experiments in mice and men provide compelling evidence that lack of sleep leads to excessive production and transport of TP in the brain. The mechanism for these findings is not entirely clear, but it is known that TP is released when neurons depolarize and synapses are actively firing. During sleep, the brain is less metabolically active than during wakefulness, so it is possible that sleep disruption could result in excessive TP release that then is not cleared due to lack of sleep.
Since TP appears to play a significant role in the pathogenesis of AD and other tauopathies, it follows that avoiding sleeplessness can be used to prevent or even treat AD and other tauopathies. This so-called “chronotherapy” uses exposure to bright light, exercise, and melatonin to help subjects with PD regulate their sleep-wake disturbance and improve their quality of life [3]. For the rest of us, it is probably best to take Shakespeare’s word for it: When weary with toil, haste to our bed seeking Nature’s soft nurse, O sleep! O gentle sleep!
References
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
2. Noble W, Spires-Jones TL. Sleep well to slow Alzheimer's progression? Science. 2019 Feb 22;363(6429):813-814
3. Fifel K, Videnovic A. Chronotherapies for Parkinson's disease. Prog Neurobiol. 2019 Mar;174:16-27
It turns out that sleep, “that balm of hurt minds”, may actually help “raze out the written troubles of the brain”—to use Shakespeare’s description in Macbeth. At least, that’s what a 2019 paper published in Science [1] and its accompanying editorial [2] suggest. A group of scientists from four universities reported that a lack of sleep may enhance the deposition of Tau protein (TP) in the brain. TP is a cellular protein found in the central nervous system that helps stabilize microtubules, structures that serve as the neuron’s internal skeleton. TP may be involved in the pathogenesis of Alzheimer’s disease (AD) as well as other diseases called “tauopathies,” which include Parkinson’s disease and chronic traumatic encephalopathy that afflicts boxers and NFL players. In these diseases, aggregates of TP and beta-amyloid are deposited in the brain, forming neurofibrillary tangles.
Cognitive decline is more strongly associated with TP deposits than with beta-amyloid aggregates [1], suggesting that TP plays a more prominent pathogenic role.
Using micro-brain surgery techniques and stereotaxic equipment, researchers prodded mice with their fingers to keep them awake, while measuring the production of TP in the animals’ cerebral interstitial fluid, the watery substance between brain cells. During the procedure, mice were put under general anesthesia, but when they awoke, they were able to move around freely in their cages, eat, and sleep. The findings were dramatic: while mice were kept awake, the production of TP increased by 50%. Authors then examined the transportation of TP within the brain by injecting recombinant TP into the mice’s brain hippocampus. After 28 days of sleep deprivation they found increased spreading of TP to other brain regions connected to the hippocampus, the brain’s memory center.
Although the above experiment seems to support the hypothesis that sleeplessness raises brain TP production and transportation, there’s a rub: what if keeping mice awake by the relatively crude approach of finger-prodding may have raised brain TP by mechanisms that were unrelated to sleep deprivation? Seeking a “pure” method of inducing persistent wakefulness, the researchers embarked on a series of chemogenetic experiments. The authors used adeno-associated viruses (AAV) to stereotaxically transfect the gene for a DREADD receptor (DREADD stands for “designer receptor exclusively activated by designer drugs”) into the neurons in a part of the mouse brain’s hypothalamus that controls sleep and arousal called the supramammillary nucleus (SuM). They then gave the mice clozapine-N-oxide (CNO), a drug designed to specifically activate the DREADD receptor transfected into the SuM neurons. The mice treated in this way experienced prolonged wakefulness, during which they displayed increased TP production in brain interstitial system. Similarly, mice who were not transfected with the DREADD receptor did not experience prolonged wakefulness after administration of CNO or a placebo. These results suggest that sleep deprivation is associated with elevated TP production.
As convincing as these experiments may seem, their significance would be considerably amplified by replication of at least some of the findings in humans. Although it is highly unlikely that humans would volunteer for experiments to obtain interstitial brain fluid or submit to DREADD receptor gene transfection into the brain, authors did have access to something similar: cerebrospinal fluid (CSF) from humans who volunteered to spend three nights in a research unit while their CSF was drained through an indwelling spinal catheter. At random, the volunteers were either kept awake by the nursing staff for 36 hours or allowed to sleep. Similar to the mouse model, TP concentration in the CSF increased by more than 50% while the volunteers were kept awake.
The above experiments in mice and men provide compelling evidence that lack of sleep leads to excessive production and transport of TP in the brain. The mechanism for these findings is not entirely clear, but it is known that TP is released when neurons depolarize and synapses are actively firing. During sleep, the brain is less metabolically active than during wakefulness, so it is possible that sleep disruption could result in excessive TP release that then is not cleared due to lack of sleep.
Since TP appears to play a significant role in the pathogenesis of AD and other tauopathies, it follows that avoiding sleeplessness can be used to prevent or even treat AD and other tauopathies. This so-called “chronotherapy” uses exposure to bright light, exercise, and melatonin to help subjects with PD regulate their sleep-wake disturbance and improve their quality of life [3]. For the rest of us, it is probably best to take Shakespeare’s word for it: When weary with toil, haste to our bed seeking Nature’s soft nurse, O sleep! O gentle sleep!
References
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
2. Noble W, Spires-Jones TL. Sleep well to slow Alzheimer's progression? Science. 2019 Feb 22;363(6429):813-814
3. Fifel K, Videnovic A. Chronotherapies for Parkinson's disease. Prog Neurobiol. 2019 Mar;174:16-27
