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 journalArticlepeer-review

263 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 languageEnglish
Pages (from-to)80-884
Number of pages805
JournalScience
Volume363
Issue number6429
DOIs
StatePublished - 2019

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