title: Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer's Disease: From Early to Advanced Pathological Stages.
abstract: In addition to cognitive decline, individuals affected by Alzheimer's disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured. At all ages, TgCRND8 mice showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep during the resting and active phases. Increased wakefulness in TgCRND8 mice was accompanied by a shift in the waking power spectrum towards fast frequency oscillations in the beta (14-20 Hz) and low gamma range (20-50 Hz). Given the phenotype of hyperarousal observed in TgCRND8 mice, the role of noradrenergic transmission in the promotion of arousal, and previous work reporting an early disruption of the noradrenergic system in TgCRND8, we tested the effects of the alpha-1-adrenoreceptor antagonist, prazosin, on sleep-wake patterns in TgCRND8 and non-transgenic (NTg) mice. We found that a lower dose (2 mg/kg) of prazosin increased NREM sleep in NTg but not in TgCRND8 mice, whereas a higher dose (5 mg/kg) increased NREM sleep in both genotypes, suggesting altered sensitivity to noradrenergic blockade in TgCRND8 mice. Collectively our results demonstrate that amyloidosis in TgCRND8 mice is associated with sleep-wake cycle dysfunction, characterized by hyperarousal, validating this model as a tool towards understanding the relationship between β-amyloid overproduction and disrupted sleep-wake patterns in AD.
authors.affiliation: Douglas Mental Health University Institute, Dept. of Psychiatry, McGill University, Montreal, Quebec, H4H 1R3, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Colby-Milley
authors.affiliation: Douglas Mental Health University Institute, Dept. of Psychiatry, McGill University, Montreal, Quebec, H4H 1R3, Canada.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Cavanagh
authors.affiliation: Douglas Mental Health University Institute, Dept. of Psychiatry, McGill University, Montreal, Quebec, H4H 1R3, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Jego
authors.affiliation: Douglas Mental Health University Institute, Dept. of Psychiatry, McGill University, Montreal, Quebec, H4H 1R3, Canada.
authors.forename: John C S
authors.initials: JC
authors.lastname: Breitner
authors.affiliation: Douglas Mental Health University Institute, Dept. of Psychiatry, McGill University, Montreal, Quebec, H4H 1R3, Canada.
authors.forename: Rémi
authors.initials: R
authors.lastname: Quirion
authors.affiliation: Douglas Mental Health University Institute, Dept. of Psychiatry, McGill University, Montreal, Quebec, H4H 1R3, Canada; Inselspital, Bern University Hospital, Bern University, Dept. of Neurology, Freiburgstrasse, 18, 3010 Bern, Switzerland.
authors.forename: Antoine
authors.initials: A
authors.lastname: Adamantidis
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D000686:Amyloidosis / Q000209:etiology* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017286:Polysomnography; D012890:Sleep / Q000502:physiology*; D012893:Sleep Wake Disorders / Q000150:complications* / Q000473:pathology; D014851:Wakefulness / Q000502:physiology*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor