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The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans
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Abstract
Sleep may protect the brain from AD: Two main proteins accumulate in the brain in Alzheimer's disease (AD), β-amyloid (Aβ) and tau. Aβ appears to instigate AD, but tau appears to drive brain damage and cognitive decline. Sleep deprivation is known to increase Aβ acutely and chronically. Now, Holth et al. show that chronic sleep deprivation strongly increases tau acutely over hours and also drives tau pathology spreading in the brains of mice and humans (see the Perspective by Noble and Spires-Jones). Thus, sleep appears to have a direct protective effect on a key protein that drives AD pathology. Science , this issue p. 880 ; see also p. 813
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“Chronic sleep deprivation was shown to enhance Aβ plaque deposition and pathological tau spreading in mice [420].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [420]
In the citing paper
“A recent study shows that tau levels in mouse ISF and human CSF are higher during normal wakefulness versus sleep. Chronic SD increases pathological tau spreading in mice. In addition, chemogenetic induction of wake states in mice significantly increases both ISF Aβ and tau [420].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [420]
In the citing paper
“amyloid-ß, tau and α-synuclein are all present at higher levels in the brain extracellular fluid and CSF during wakefulness than during sleep, and sleep deprivation increases their levels further (106–108).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [108]
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“In that regard, recent advances in neuroimaging have provided multiple approaches to map the human glymphatic system, and hence to assess its functional competence in the context of disease, as well as of the effects thereof on sleep-dependent glymphatic cyclicity (72, 73, 108).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [108]
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Metadata
- Authors
- Holth, J. K., Fritschi, S. K., Wang, C., Pedersen, N. P., Cirrito, J. R., Mahan, T. E., Finn, M. B., Manis, M., Geerling, J. C., Fuller, P. M., Lucey, B. P., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Emory University (US)
- University of Iowa Hospitals and Clinics (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Holth, Jerrah K.
- Fritschi, Sarah K.
- Holtzman, David M.
- ORCID
- Venue
- Science
- Published
- 2019-02-22
- Volume
- 363
- Issue
- 6429
- Pages
- 880-884
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6410369
- OpenAlex
- W2912003143
- Cited by
- 813
- References
- 33
- Citations by year
- 2026: 117 · 2025: 121 · 2024: 128 · 2023: 115 · 2022: 98 · 2021: 98 · 2020: 87 · 2019: 49
- FWCI
- 56.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Aging (AG047999, AG054863, AG05681, AG26276)
- National Institute of Neurological Disorders and Stroke (NS074969, NS073613, K08NS105929, NS089381)
- National Center for Advancing Translational Sciences (TR000448, TR000450)
- BrightFocus Foundation (A2017114F)
- Deutsche Forschungsgemeinschaft (3625/1-1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Keywords
- sleep-wake cycle, tau protein, cerebrospinal fluid, interstitial fluid, chronic sleep deprivation, Alzheimer's disease, amyloid-beta, tau pathology
- MeSH terms
- Animals, Brain, Circadian Rhythm, Female, Male, Mice, Transgenic, Sleep, Sleep Deprivation, Wakefulness, Amyloid beta-Peptides, tau Proteins, Extracellular Fluid, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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