title: Orexin Impairs the Phagocytosis and Degradation of Amyloid-β Fibrils by Microglial Cells.
abstract: Intracranial accumulation of amyloid-β (Aβ) is a characteristic finding of Alzheimer's disease (AD). It is thought to be the result of Aβ overproduction by neurons and impaired clearance by several systems, including degradation by microglia. Sleep disturbance is now considered a risk factor for AD, but studies focusing on how sleep modulates microglial handling of Aβ have been scarce.
  
  
  
  To determine whether phagocytosis and degradation of extracellular Aβ fibrils by BV2 microglial cells were impaired by treatment with orexin-A/B, a major modulator of the sleep-wake cycle, which may mimic sleep deprivation conditions.
  
  
  
  BV2 cells were treated with orexin and Aβ for various durations and phagocytic and autophagic processes for degradation of extracellular Aβ were examined.
  
  
  
  After treatment with orexin, the formation of actin filaments around Aβ fibrils, which is needed for phagocytosis, was impaired, and phagocytosis regulating molecules such as PI3K, Akt, and p38-MAPK were downregulated in BV2 cells. Orexin also suppressed autophagic flux, through disruption of the autophagosome-lysosome fusion process, resulting in impaired Aβ degradation in BV2 cells.
  
  
  
  Our results demonstrate that orexin can hinder clearance of Aβ through the suppression of phagocytosis and autophagic flux in microglia. This is a novel mechanism linking AD and sleep, and suggests that attenuated microglial function, due to sleep deprivation, may increase Aβ accumulation in the brain.
authors.affiliation: Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Korea.|National Institute of Dementia, Seongnam, Korea.
authors.forename: Hoyoung
authors.initials: H
authors.lastname: An
authors.affiliation: Department of Brain Science, University of Ulsan College of Medicine, Seoul, Korea.|Alzheimer's Disease Experts Lab (ADEL), Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Mi-Hyang
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Department of Brain Science, University of Ulsan College of Medicine, Seoul, Korea.|Alzheimer's Disease Experts Lab (ADEL), Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Dong-Hou
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Seockhoon
authors.initials: S
authors.lastname: Chung
authors.affiliation: Department of Brain Science, University of Ulsan College of Medicine, Seoul, Korea.|Alzheimer's Disease Experts Lab (ADEL), Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Yoon
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002461:Cell Line, Transformed; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D000068797:Orexins / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D008164:Luminescent Proteins; D008869:Microtubule-Associated Proteins; D000068797:Orexins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C480860:Map1lc3b protein, mouse
keywords: Actin; Alzheimer’s disease; dementia; orexin; sleep