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JOURNAL ARTICLE

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
Science 2019 February 22, 363 (6429): 880-884
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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 Aβ 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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