The DOI matches its Crossref record; 32 of the 33 references it cites were found in a registry or an index.
The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans
Open accessPublished version of a preprint
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]
In the citing paper
“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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Cites
Sleep Drives Metabolite Clearance from the Adult Brain
Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., et al. (2013) · Science · doi:10.1126/science.1241224 · Cited by 5,411
Transmission and spreading of tauopathy in transgenic mouse brain
Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A. K., Beibel, M., Staufenbiel, M., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1901 · Cited by 1,803
Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh019 · Cited by 1,575
Amyloid-β Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle
Kang, J.-E., Lim, M. M., Bateman, R. J., Lee, J. J., Smyth, L. P., Cirrito, J. R., Fujiki, N., Nishino, S., & Holtzman, D. M. (2009) · Science · doi:10.1126/science.1180962 · Cited by 1,565
Self-citationPropagation of Tau Pathology in a Model of Early Alzheimer's Disease
de Calignon, A., Polydoro, M., Suárez-Calvet, M., William, C., Adamowicz, D. H., Kopeikina, K. J., Pitstick, R., Sahara, N., Ashe, K. H., Carlson, G. A., et al. (2012) · Neuron · doi:10.1016/j.neuron.2011.11.033 · Cited by 1,427
Tau pathology and neurodegeneration
Spillantini, M. G., & Goedert, M. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70090-5 · Cited by 1,133
Trans-Synaptic Spread of Tau Pathology In Vivo
Liu, L., Drouet, V., Wu, J., Witter, M. P., Small, S. A., Clelland, C. L. T., & Duff, K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031302 · Cited by 994
Neuronal activity regulates the regional vulnerability to amyloid-β deposition
Bero, A. W., Yan, P., Roh, J. H., Cirrito, J. R., Stewart, F. R., Raichle, M. E., Lee, J.-M., & Holtzman, D. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2801 · Cited by 880
Self-citationVyazovskiy, V. V., Cirelli, C., Pfister-Genskow, M., Faraguna, U., & Tononi, G. (2008) · Nature Neuroscience · doi:10.1038/nn2035 · Cited by 837 · cited 1×
“As neuronal synaptic strength/connectivity is higher during wakefulness than during sleep (11, 12), we asked whether tau levels in the brain interstitial fluid (ISF) varied with the sleep-wake cycle.”
BackgroundNeuronal activity enhances tau propagation and tau pathology in vivo
Wu, J. W., Hussaini, S. A., Bastille, I. M., Rodriguez, G. A., Mrejeru, A., Rilett, K., Sanders, D. W., Cook, C., Fu, H., Boonen, R. A. C. M., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4328 · Cited by 820
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1 of the 33 references couldn’t be matched to a known paper.
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Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204
Self-citationCoupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep
Fultz, N. E., Bonmassar, G., Setsompop, K., Stickgold, R. A., Rosen, B. R., Polimeni, J. R., & Lewis, L. D. (2019) · Science · doi:10.1126/science.aax5440 · Cited by 1,197
Glymphatic failure as a final common pathway to dementia
Nedergaard, M., & Goldman, S. A. (2020) · Science · doi:10.1126/science.abb8739 · Cited by 1,145
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994
Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways
Greenberg, S. M., Bacskai, B. J., Hernandez-Guillamon, M., Pruzin, J., Sperling, R., & van Veluw, S. J. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-019-0281-2 · Cited by 947
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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