title: Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer's disease.
abstract: Age-related aggregation of amyloid-β (Aβ) is an upstream pathological event in Alzheimer's disease (AD) pathogenesis, and it disrupts the sleep-wake cycle. The amount of sleep declines with aging and to a greater extent in AD. Poor sleep quality and insufficient amounts of sleep have been noted in humans with preclinical evidence of AD. However, how the amount and quality of sleep affects Aβ aggregation is not yet well understood. Orexins (hypocretins) initiate and maintain wakefulness, and loss of orexin-producing neurons causes narcolepsy. We tried to determine whether orexin release or secondary changes in sleep via orexin modulation affect Aβ pathology. Amyloid precursor protein (APP)/Presenilin 1 (PS1) transgenic mice, in which the orexin gene is knocked out, showed a marked decrease in the amount of Aβ pathology in the brain with an increase in sleep time. Focal overexpression of orexin in the hippocampus in APP/PS1 mice did not alter the total amount of sleep/wakefulness and the amount of Aβ pathology. In contrast, sleep deprivation or increasing wakefulness by rescue of orexinergic neurons in APP/PS1 mice lacking orexin increased the amount of Aβ pathology in the brain. Collectively, modulation of orexin and its effects on sleep appear to modulate Aβ pathology in the brain.
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, South Korea.
authors.forename: Jee Hoon
authors.initials: JH
authors.lastname: Roh
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Finn
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
authors.forename: Floy R
authors.initials: FR
authors.lastname: Stewart
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mahan
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
authors.forename: Ashish
authors.initials: A
authors.lastname: Heda
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
authors.forename: B Joy
authors.initials: BJ
authors.lastname: Snider
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305.
authors.forename: Luis
authors.initials: L
authors.lastname: de Lecea
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 holtzman@neuro.wustl.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002908:Chronic Disease; D002940:Circadian Rhythm / Q000502:physiology; D005822:Genetic Vectors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D018345:Mice, Knockout; D009479:Neuropeptides / Q000172:deficiency / Q000378:metabolism*; D000068797:Orexins; D053764:Presenilin-1 / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012890:Sleep / Q000502:physiology*; D012892:Sleep Deprivation / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D014851:Wakefulness / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D053764:Presenilin-1; C580804:presenilin 1, mouse