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

Science. 2019 Feb 22;363(6429):880-884. doi: 10.1126/science.aav2546. Epub 2019 Jan 24.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyloid beta-Peptides / analysis
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / metabolism*
  • Circadian Rhythm*
  • Extracellular Fluid / chemistry*
  • Extracellular Fluid / metabolism
  • Female
  • Male
  • Mice
  • Mice, Transgenic
  • Sleep / physiology*
  • Sleep Deprivation / cerebrospinal fluid
  • Sleep Deprivation / metabolism*
  • Wakefulness / genetics
  • Wakefulness / physiology*
  • tau Proteins / analysis*
  • tau Proteins / cerebrospinal fluid*
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • MAPT protein, human
  • Mapt protein, mouse
  • tau Proteins