title: Effects of growth hormone-releasing hormone on sleep and brain interstitial fluid amyloid-β in an APP transgenic mouse model.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by impairment of cognitive function, extracellular amyloid plaques, intracellular neurofibrillary tangles, and synaptic and neuronal loss. There is substantial evidence that the aggregation of amyloid β (Aβ) in the brain plays a key role in the pathogenesis of AD and that Aβ aggregation is a concentration dependent process. Recently, it was found that Aβ levels in the brain interstitial fluid (ISF) are regulated by the sleep-wake cycle in both humans and mice; ISF Aβ is higher during wakefulness and lower during sleep. Intracerebroventricular infusion of orexin increased wakefulness and ISF Aβ levels, and chronic sleep deprivation significantly increased Aβ plaque formation in amyloid precursor protein transgenic (APP) mice. Growth hormone-releasing hormone (GHRH) is a well-documented sleep regulatory substance which promotes non-rapid eye movement sleep. GHRHR(lit/lit) mice that lack functional GHRH receptor have shorter sleep duration and longer wakefulness during light periods. The current study was undertaken to determine whether manipulating sleep by interfering with GHRH signaling affects brain ISF Aβ levels in APPswe/PS1ΔE9 (PS1APP) transgenic mice that overexpress mutant forms of APP and PSEN1 that cause autosomal dominant AD. We found that intraperitoneal injection of GHRH at dark onset increased sleep and decreased ISF Aβ and that delivery of a GHRH antagonist via reverse-microdialysis suppressed sleep and increased ISF Aβ. The diurnal fluctuation of ISF Aβ in PS1APP/GHRHR(lit/lit) mice was significantly smaller than that in PS1APP/GHRHR(lit/+) mice. However despite decreased sleep in GHRHR deficient mice, this was not associated with an increase in Aβ accumulation later in life. One of several possibilities for the finding is the fact that GHRHR deficient mice have GHRH-dependent but sleep-independent factors which protect against Aβ deposition.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States. Electronic address: liaof@neuro.wustl.edu.
authors.forename: Fan
authors.initials: F
authors.lastname: Liao
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States. Electronic address: zhangt@neuro.wustl.edu.
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States. Electronic address: mahant@neuro.wustl.edu.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mahan
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States. Electronic address: jiangh@neuro.wustl.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States. Electronic address: holtzman@neuro.wustl.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis; D012890:Sleep / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D013007:Growth Hormone-Releasing Hormone
keywords: Alzheimer’s disease; Amyloid-β; Growth hormone–releasing hormone; Sleep