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

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 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.

Slow‐wave sleep and motor progression in Parkinson disease

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“…4 Although, in contrast to beta-amyloid, alpha-synuclein primarily accumulates intracellularly, glymphatic clearance could theoretically slow its extracellular propagation, 19 and novel evidence suggests that sleep-wake dynamics might regulate levels of alphasynuclein in cerebrospinal fluid. 20 However, we consider our finding as preliminary due to limitations. Owing to the retrospective study design, we observed data variability (eg, 31 of 129 patients were drugnaive at baseline and none at follow-up).…”

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

“…From this follows that sleep might be required for "waste" removal from the brain. In addition, levels of ISF and CSF tau relate to neuronal activity and the sleep-wake cycle rather than to paravascular clearance [71]. The role of Aqp4 in glymphatic function is, however, still a matter of discussion.…”

Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial

“…Sleep disturbance and insomnia are common in Alzheimer's disease (AD), affecting ≈40% of patients . There is emerging evidence that poor sleep may contribute to the development of AD and impair memory function . Options for effective pharmacological treatment of insomnia in AD are limited, with inconsistent or poor‐quality evidence for efficacy of melatonin, second‐generation antipsychotics (which are primarily used to target other neuropsychiatric and behavioral symptoms associated with AD), and sedating antidepressants .…”

“…1 There is emerging evidence that poor sleep may contribute to the development of AD and impair memory function. [2][3][4][5][6][7][8][9] Options for effective pharmacological treatment of insomnia in AD are limited, with inconsistent or poor-quality evidence for efficacy of melatonin, [10][11][12][13] second-generation antipsychotics (which are primarily used to target other neuropsychiatric…”