title: microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain.
abstract: Dysregulation of amyloid-β (Aβ) metabolism is critical for Alzheimer's disease (AD) pathogenesis. Mounting evidence suggests that apolipoprotein E (ApoE) is involved in Aβ metabolism. ATP-binding cassette transporter A1 (ABCA1) is a key regulator of ApoE lipidation, which affects Aβ levels. Therefore, identifying regulatory mechanisms of ABCA1 expression in the brain may provide new therapeutic targets for AD. Here, we demonstrate that microRNA-33 (miR-33) regulates ABCA1 and Aβ levels in the brain. Overexpression of miR-33 impaired cellular cholesterol efflux and dramatically increased extracellular Aβ levels by promoting Aβ secretion and impairing Aβ clearance in neural cells. In contrast, genetic deletion of mir-33 in mice dramatically increased ABCA1 levels and ApoE lipidation, but it decreased endogenous Aβ levels in cortex. Most importantly, pharmacological inhibition of miR-33 via antisense oligonucleotide specifically in the brain markedly decreased Aβ levels in cortex of APP/PS1 mice, representing a potential therapeutic strategy for AD.
  
  
  CONCLUSIONS
  Brain lipid metabolism, in particular Apolipoprotein E (ApoE) lipidation, is critical to Aβ metabolism and Alzheimer's disease (AD). Brain lipid metabolism is largely separated from the periphery due to blood-brain barrier and different repertoire of lipoproteins. Therefore, identifying the novel regulatory mechanism of brain lipid metabolism may provide a new therapeutic strategy for AD. Although there have been studies on brain lipid metabolism, its regulation, in particular by microRNAs, is relatively unknown. Here, we demonstrate that inhibition of microRNA-33 increases lipidation of brain ApoE and reduces Aβ levels by inducing ABCA1. We provide a unique approach for AD therapeutics to increase ApoE lipidation and reduce Aβ levels via pharmacological inhibition of microRNA in vivo.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Horie
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Jack M
authors.initials: JM
authors.lastname: Burchett
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Restivo
authors.affiliation: Vascular Biology and Therapeutics Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: Noemi
authors.initials: N
authors.lastname: Rotllan
authors.affiliation: Vascular Biology and Therapeutics Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Ramírez
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Verghese
authors.affiliation: Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, Osaka 565-8565, Japan.
authors.forename: Masafumi
authors.identifier: http://orcid.org/0000-0002-7102-4048
authors.initials: M
authors.lastname: Ihara
authors.affiliation: Departments of Neuroscience and Neurology, Georgetown University Medical Center, Washington, DC 20007, and.
authors.forename: Hyang-Sook
authors.initials: HS
authors.lastname: Hoe
authors.affiliation: Regulus Therapeutics, San Diego, California 92121.
authors.forename: Christine
authors.identifier: http://orcid.org/0000-0001-6399-1698
authors.initials: C
authors.lastname: Esau
authors.affiliation: Vascular Biology and Therapeutics Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110, kim.jungsu@mayo.edu kohono@kuhp.kyoto-u.ac.jp cirritoj@neuro.wustl.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan, kim.jungsu@mayo.edu kohono@kuhp.kyoto-u.ac.jp cirritoj@neuro.wustl.edu.
authors.forename: Koh
authors.identifier: http://orcid.org/0000-0002-4163-980X
authors.initials: K
authors.lastname: Ono
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110, kim.jungsu@mayo.edu kohono@kuhp.kyoto-u.ac.jp cirritoj@neuro.wustl.edu.
authors.forename: Jungsu
authors.identifier: http://orcid.org/0000-0002-6931-8581
authors.initials: J
authors.lastname: Kim
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D008969:Molecular Sequence Data
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse
keywords: ABCA1; Alzheimer's disease; ApoE; abeta; miR-33