title: Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer's disease pathology.
abstract: Aggregation of β-amyloid (Aβ) in the brain begins to occur years before the clinical onset of Alzheimer's disease (AD). Before Aβ aggregation, concentrations of extracellular soluble Aβ in the interstitial fluid (ISF) space of the brain, which are regulated by neuronal activity and the sleep-wake cycle, correlate with the amount of Aβ deposition in the brain seen later. The amount and quality of sleep decline with normal aging and to a greater extent in AD patients. How sleep quality as well as the diurnal fluctuation in Aβ change with age and Aβ aggregation is not well understood. We report a normal sleep-wake cycle and diurnal fluctuation in ISF Aβ in the brain of the APPswe/PS1δE9 mouse model of AD before Aβ plaque formation. After plaque formation, the sleep-wake cycle markedly deteriorated and diurnal fluctuation of ISF Aβ dissipated. As in mice, diurnal fluctuation of cerebrospinal fluid Aβ in young adult humans with presenilin mutations was also markedly attenuated after Aβ plaque formation. Virtual elimination of Aβ deposits in the mouse brain by active immunization with Aβ(42) normalized the sleep-wake cycle and the diurnal fluctuation of ISF Aβ. These data suggest that Aβ aggregation disrupts the sleep-wake cycle and diurnal fluctuation of Aβ. Sleep-wake behavior and diurnal fluctuation of Aβ in the central nervous system may be functional and biochemical indicators, respectively, of Aβ-associated pathology.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jee Hoon
authors.initials: JH
authors.lastname: Roh
authors.forename: Yafei
authors.initials: Y
authors.lastname: Huang
authors.forename: Adam W
authors.initials: AW
authors.lastname: Bero
authors.forename: Tom
authors.initials: T
authors.lastname: Kasten
authors.forename: Floy R
authors.initials: FR
authors.lastname: Stewart
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Bateman
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000473:pathology* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology*; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000378:metabolism; D005799:Genes, Dominant / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007114:Immunization; D007773:Lactates / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D053763:Presenilins / Q000235:genetics; D012890:Sleep / Q000502:physiology*; D013997:Time Factors; D014851:Wakefulness / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D007773:Lactates; D053763:Presenilins