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

• Published in: Science (American Association for the Advancement of Science) Vol. 363; no. 6429; pp. 880 - 884
• Main Authors: Holth, Jerrah K., Fritschi, Sarah K., Wang, Chanung, Pedersen, Nigel P., Cirrito, John R., Mahan, Thomas E., Finn, Mary Beth, Manis, Melissa, Geerling, Joel C., Fuller, Patrick M., Lucey, Brendan P., Holtzman, David M.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 22.02.2019; The American Association for the Advancement of Science
• Subjects: Alzheimer's disease; Amyloid beta-Peptides - analysis; Amyloid beta-Peptides - cerebrospinal fluid; Amyloid beta-Peptides - metabolism; Animals; Brain; Brain - metabolism; Brain damage; Brain injury; Cerebrospinal fluid; Circadian Rhythm; Cognitive ability; Extracellular Fluid - chemistry; Extracellular Fluid - metabolism; Female; Male; Mice; Mice, Transgenic; Neurodegeneration; Neurodegenerative diseases; Neurological Impairments; Pathology; Proteins; Senile plaques; Sleep; Sleep - physiology; Sleep and wakefulness; Sleep deprivation; Sleep Deprivation - cerebrospinal fluid; Sleep Deprivation - metabolism; Spires; Spreading; Tau protein; tau Proteins - analysis; tau Proteins - cerebrospinal fluid; tau Proteins - metabolism; Wakefulness; Wakefulness - genetics; Wakefulness - physiology; β-Amyloid
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aav2546

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.