Sleep Drives Metabolite Clearance from the Adult Brain
Open accessAbstract
Taking Out the Trash: The purpose of sleep remains mysterious. Using state-of-the-art in vivo two-photon imaging to directly compare two arousal states in the same mouse, Xie et al. (p. 373 ; see the Perspective by Herculano-Houzel ) found that metabolic waste products of neural activity were cleared out of the sleeping brain at a faster rate than during the awake state. This finding suggests a mechanistic explanation for how sleep serves a restorative function, in addition to its well-described effects on memory consolidation.
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Sleep involves the brain-wide flushing of metabolites with cerebral spinal fluid via the glymphatic system.
“This was the discovery of the brain's glymphatic system, showing that sleep involves the brain-wide flushing of metabolites with cerebral spinal fluid.28”
From The overfitted brain: Dreams evolved to assist generalization (2021) · cites this paper as [28]
The Abstract reports that sleep increased cerebrospinal-fluid exchange with interstitial fluid and accelerated β-amyloid clearance in mice, supporting the flushing description. But the paper describes the glymphatic system as an already named pathway (Abstract, passage 3); its finding was the sleep-related change in clearance, not the discovery of the system itself. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSleep, especially during slow wave activity, has the goal of waste clearance, and this is at least partly behind sleep's restorative aspect.
“This led to the theory that sleep, especially during slow wave activity, had the goal of waste clearance and this is at least partly behind sleep's restorative aspect.”
From The overfitted brain: Dreams evolved to assist generalization (2021) · cites this paper as [28]
The paper proposes that clearing metabolic waste may be a function of sleep and may help explain its restorative effect; it also reports faster β-amyloid clearance in sleeping than awake mice. It observes increased slow-wave activity alongside increased tracer influx, but does not establish that clearance occurs especially during slow-wave activity. The indexed passages are labeled Abstract; no page numbers are available. (LLM, conf=0.85)
Experimental — accuracy not yet measuredUnder physiological conditions, perivascular interstitial fluid flow contributes to 15-20% of Aβ clearance from the mouse brain.
“For example, transport studies using radiolabeled and unlabeled Alzheimer's A 𝛃 peptide have shown that under physiological conditions, the perivascular ISF flow contributes to 15-20% of A 𝛃 clearance from the mouse brain (58, 535, 659), whereas 8085% is removed by transvascular BBB transport.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [659]
The indexed passage labeled Abstract (page unavailable) describes perivascular CSF–ISF exchange that removes Aβ from mouse brain. It does not give the claimed 15–20% share under physiological conditions or the sentence’s 80–85% share for BBB transport; its separate estimate is that as much as 65% of exogenously delivered Aβ is cleared by the glymphatic system. (LLM, conf=0.86)
Experimental — accuracy not yet measuredUnder physiological conditions, 80-85% of Aβ is removed from the mouse brain by transvascular blood-brain barrier transport.
“whereas 8085% is removed by transvascular BBB transport.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [659]
The paper states that Aβ can be removed from the CNS by receptor-mediated transport across the blood-brain barrier (section labeled Abstract; page unavailable). It does not say that this route accounts for 80–85% of Aβ removal under physiological conditions; the proportion it discusses instead is up to 65% of exogenously delivered Aβ cleared by the glymphatic system. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNatural sleep in animal studies is associated with increased size of the interstitial space, facilitating increased convective exchange of CSF with interstitial fluid and clearance of macromolecules.
“Natural sleep in animal studies has been shown to associate with increased size of the interstitial space, facilitating increased convective exchange of CSF with interstitial fluid and clearance of macromolecules (23).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [23]
Sleep increases CSF circulation and accelerates transport and clearance of Aβ.
“Sleep can increase CSF circulation and accelerate transport and clearance of Aβ [419].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [419]
The glymphatic system clears protein waste from the brain and is mostly active during sleep.
“The glymphatic system, which clears the brain of protein waste products, is mostly active during sleep.”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [35]
Brain fluid transport initiates and proceeds during NREM sleep, and CSF tracer influx correlates with EEG slow wave activity prevalence.
“Brain fluid transport initiates and proceeds during NREM sleep, and CSF tracer influx correlates with the prevalence of EEG slow wave activity (35, 36).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [35]
Glymphatic flow appears to stop with the onset of wakefulness.
“Fluid flow through the glymphatic system is thus inextricably linked with sleep, to the extent that flow appears to stop with the onset of wakefulness.”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [35]
Glymphatic clearance is enabled by sleep and suppressed during wakefulness.
“glymphatic clearance is temporally regulated and cyclically so, in that fluid transport is enabled by sleep and suppressed during wakefulness.”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [35]
Sleep is restorative and involves clearance of metabolites from the brain.
“This finding is consistent with several studies suggesting that the function of sleep is restorative and involves metabolite clearance from the brain (9), and that sleep restores antioxidant balance in peripheral tissues (46).”
From Oxalic acid and diacylglycerol 36:3 are cross-species markers of sleep debt (2015) · cites this paper as [9]
Neurons, glia cells, and nerve fibers themselves can synthesize cytokines and chemokines, demonstrating a further pathway of brain-to-immune signaling.
“Neurons, glia cells, and nerve fibers themselves can synthesize cytokines and chemokines, demonstrating a further pathway of brain-to-immune signaling (70, 592).”
From The Sleep-Immune Crosstalk in Health and Disease (2019) · cites this paper as [592]
During sleep, the glymphatic system exchanges cerebrospinal fluid with interstitial fluid and clears amyloid-β.
“during sleep, the glymphatic system285 exchanges cerebrospinal fluid with interstitial fluid and clears Aβ286”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [285]
In mice, wakefulness suppresses the outflow of cerebral spinal fluid from the brain, whereas sleep leads to an increase in convective fluxes of fluid, effectively promoting the clearance of neurotoxic metabolites, including Aβ.
“A landmark study in mice demonstrating that wakefulness suppresses the outflow of cerebral spinal fluid from the brain, whereas sleep leads to an increase in convective fluxes of fluid, effectively promoting the clearance of neurotoxic metabolics, including Aβ.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [285]
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- Authors
- Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., Takano, T., Deane, R., & Nedergaard, M.
- Affiliations
- University of Rochester Medicine (US)
- NYU Langone Health (US)
- Corresponding author
- Xie, Lulu
- Kang, Hongyi
- Nedergaard, Maiken
- ORCID
- Venue
- Science
- Published
- 2013-10-18
- Volume
- 342
- Issue
- 6156
- Pages
- 373-377
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3880190
- OpenAlex
- W2163225965
- Cited by
- 5,411
- References
- 47
- Citations by year
- 2026: 656 · 2025: 664 · 2024: 528 · 2023: 541 · 2022: 466 · 2021: 462 · 2020: 457 · 2019: 371 · 2018: 310 · 2017: 308 · 2016: 239 · 2015: 243 · 2014: 142 · 2013: 18 · 2012: 1
- FWCI
- 116.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Israel Science Foundation
- National Institute of Neurological Disorders and Stroke (R01NS078304, NS028642, R01NS078167, R01NS075177, NS078167, R01NS028642, NS078304))
- National Institute of Dental and Craniofacial Research (R01DE022743)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- sleep, cerebrospinal fluid, interstitial fluid, brain waste clearance, amyloid-beta clearance, interstitial space, metabolic homeostasis, anesthesia, two-photon imaging
- MeSH terms
- Quaternary Ammonium Compounds, Animals, Brain, Cerebral Cortex, Cerebrospinal Fluid, Diffusion, Electroencephalography, Extracellular Space, Male, Mice, Inbred C57BL, Receptors, Adrenergic, Sleep, Wakefulness, Amyloid beta-Peptides, Adrenergic Antagonists, Neurodegenerative Diseases, Intracellular Space, Mice
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