The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans

Jerrah K. Holth; Sarah K. Fritschi; Chanung Wang; Nigel P. Pedersen; John R. Cirrito; Thomas E. Mahan; Mary Beth Finn; Melissa Manis; Joel C. Geerling; Patrick M. Fuller; Brendan P. Lucey; David M. Holtzman

doi:10.1126/science.aav2546

The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans

Jerrah K. Holth, Sarah K. Fritschi, Chanung Wang, Nigel P. Pedersen, John R. Cirrito, Thomas E. Mahan, Mary Beth Finn, Melissa Manis, Joel C. Geerling, Patrick M. Fuller, Brendan P. Lucey, David M. Holtzman

Research output: Contribution to journal › Article › peer-review

477 Scopus citations

Abstract

The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer's disease (AD). Furthermore, chronic sleep deprivation (SD) increases Ab plaques. However, tau, not Aβ, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ∼90% during normal wakefulness versus sleep and ∼100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.

Original language	English
Pages (from-to)	80-884
Number of pages	805
Journal	Science
Volume	363
Issue number	6429
DOIs	https://doi.org/10.1126/science.aav2546
State	Published - 2019

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title = "The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans",

abstract = "The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer's disease (AD). Furthermore, chronic sleep deprivation (SD) increases Ab plaques. However, tau, not Aβ, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ∼90% during normal wakefulness versus sleep and ∼100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.",

author = "Holth, {Jerrah K.} and Fritschi, {Sarah K.} and Chanung Wang and Pedersen, {Nigel P.} and Cirrito, {John R.} and Mahan, {Thomas E.} and Finn, {Mary Beth} and Melissa Manis and Geerling, {Joel C.} and Fuller, {Patrick M.} and Lucey, {Brendan P.} and Holtzman, {David M.}",

note = "Publisher Copyright: {\textcopyright} The Authors, some rights reserved.",

year = "2019",

doi = "10.1126/science.aav2546",

language = "English",

volume = "363",

pages = "80--884",

journal = "Science",

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T1 - The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans

AU - Holth, Jerrah K.

AU - Fritschi, Sarah K.

AU - Wang, Chanung

AU - Pedersen, Nigel P.

AU - Cirrito, John R.

AU - Mahan, Thomas E.

AU - Finn, Mary Beth

AU - Manis, Melissa

AU - Geerling, Joel C.

AU - Fuller, Patrick M.

AU - Lucey, Brendan P.

AU - Holtzman, David M.

PY - 2019

Y1 - 2019

N2 - The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer's disease (AD). Furthermore, chronic sleep deprivation (SD) increases Ab plaques. However, tau, not Aβ, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ∼90% during normal wakefulness versus sleep and ∼100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.

AB - The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer's disease (AD). Furthermore, chronic sleep deprivation (SD) increases Ab plaques. However, tau, not Aβ, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ∼90% during normal wakefulness versus sleep and ∼100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.

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DO - 10.1126/science.aav2546

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SN - 0036-8075

VL - 363

SP - 80

EP - 884

JO - Science

JF - Science

IS - 6429

ER -

The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans

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