title: miR-186 is decreased in aged brain and suppresses BACE1 expression.
abstract: Accumulation of amyloid β (Aβ) in the brain is a key pathological hallmark of Alzheimer's disease (AD). Because aging is the most prominent risk factor for AD, understanding the molecular changes during aging is likely to provide critical insights into AD pathogenesis. However, studies on the role of miRNAs in aging and AD pathogenesis have only recently been initiated. Identifying miRNAs dysregulated by the aging process in the brain may lead to novel understanding of molecular mechanisms of AD pathogenesis. Here, we identified that miR-186 levels are gradually decreased in cortices of mouse brains during aging. In addition, we demonstrated that miR-186 suppresses β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) expression by directly targeting the 3'UTR of Bace1 mRNA in neuronal cells. In contrast, inhibition of endogenous miR-186 significantly increased BACE1 levels in neuronal cells. Importantly, miR-186 over-expression significantly decreased Aβ level by suppressing BACE1 expression in cells expressing human pathogenic mutant amyloid precursor protein. Taken together, our data demonstrate that miR-186 is a potent negative regulator of BACE1 in neuronal cells and it may be one of the molecular links between brain aging and the increased risk for AD during aging. We identified that miR-186 levels are gradually decreased in mouse cortices during aging. Furthermore, we demonstrated that miR-186 is a novel negative regulator of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) expression in neuronal cells. Therefore, we proposed that reduction in miR-186 levels during aging may lead to the up-regulation of BACE1 in the brain, thereby increasing a risk for Alzheimer's disease in aged individuals. Read the Editorial Highlight for this article on page 308.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.|Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.|Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA.|Neurobiology of Disease Graduate Program, Mayo Graduate School, Jacksonville, Florida, USA.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.|Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA.|Neurobiology of Disease Graduate Program, Mayo Graduate School, Jacksonville, Florida, USA.
authors.forename: Dah-Eun
authors.initials: DE
authors.lastname: Chung
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Brown
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.
authors.forename: Krystal C
authors.initials: KC
authors.lastname: Belmonte
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.|Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA.|Neurobiology of Disease Graduate Program, Mayo Graduate School, Jacksonville, Florida, USA.
authors.forename: Jungsu
authors.identifier: http://orcid.org/0000-0002-6931-8581
authors.initials: J
authors.lastname: Kim
mesh_terms: D020413:3' Untranslated Regions; D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis* / Q000235:genetics*; D001483:Base Sequence; D001923:Brain Chemistry / Q000235:genetics*; D002540:Cerebral Cortex / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D016564:Amyloid beta-Protein Precursor; C000610209:MIRN186 microRNA, mouse; D035683:MicroRNAs; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Alzheimer's disease; Aβ; BACE1; aging; miR-186; microRNA