title: Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer's disease.
abstract: During wakefulness, extracellular levels of metabolites in the brain increase. These include amyloid beta (Aβ), which contributes to the pathogenesis of Alzheimer's disease (AD). Counterbalancing their accumulation in the brain, sleep facilitates the removal of these metabolites from the extracellular space by convective flow of the interstitial fluid from the para-arterial to the para-venous space. However, when the sleep-wake cycle is disrupted (characterized by increased brain levels of the wake-promoting neuropeptide orexin and increased neural activity), the central nervous system (CNS) clearance of extracellular metabolites is diminished. Disruptions to the sleep-wake cycle have furthermore been linked to increased neuronal oxidative stress and impaired blood-brain barrier function - conditions that have also been proposed to play a role in the development and progression of AD. Notably, recent human and transgenic animal studies have demonstrated that AD-related pathophysiological processes that occur long before the clinical onset of AD, such as Aβ deposition in the brain, disrupt sleep and circadian rhythms. Collectively, as proposed in this review, these findings suggest the existence of a mechanistic interplay between AD pathogenesis and disrupted sleep-wake cycles, which is able to accelerate the development and progression of this disease.
authors.affiliation: Department of Neuroscience, Uppsala University, Sweden. Electronic address: Jonathan.Cedernaes@neuro.uu.se.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cedernaes
authors.affiliation: Center for Brain Health, NYU Langone Medical Center, New York, NY, USA. Electronic address: Ricardo.Osorio@nyumc.org.
authors.forename: Ricardo S
authors.initials: RS
authors.lastname: Osorio
authors.affiliation: NYU Sleep Disorders Center, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Varga
authors.affiliation: NYU Sleep Disorders Center, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Korey
authors.initials: K
authors.lastname: Kam
authors.affiliation: Department of Neuroscience, Uppsala University, Sweden.
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
authors.affiliation: Department of Neuroscience, Uppsala University, Sweden. Electronic address: Christian.Benedict@neuro.uu.se.
authors.forename: Christian
authors.initials: C
authors.lastname: Benedict
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D006801:Humans; D012893:Sleep Wake Disorders / Q000503:physiopathology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins
keywords: Aging; Amyloid beta; Blood brain barrier; Circadian misalignment; Neurodegeneration; Orexin; Oxidative stress; Sleep disruption; Slow-wave sleep; Tau