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

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Science  22 Feb 2019:
Vol. 363, Issue 6429, pp. 880-884
DOI: 10.1126/science.aav2546

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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


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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