title: miR-206 regulates brain-derived neurotrophic factor in Alzheimer disease model.
abstract: OBJECTIVE
  Alzheimer disease (AD) brains are deficient in brain-derived neurotrophic factor (BDNF), which regulates synaptic plasticity and memory. MicroRNAs (miRNAs) are ∼22-nucleotide small noncoding RNAs that control a variety of physiological and disease processes. Here, we show that miR-206 regulates BDNF and memory function in AD mice.
  
  
  METHODS
  Expression of miRNAs was analyzed in Tg2576 AD transgenic mice and human AD brain samples. Regulation of BDNF by a selected miRNA was validated by in silico prediction, target gene luciferase assay, and dendritic spine responses in neurons. AM206, a neutralizing inhibitor of miR-206 (antagomir), was injected into the third ventricle of Tg2576 mice, after which memory function, synaptogenesis, neurogenesis, and target gene expression were assessed. For noninvasive delivery, antagomirs were administered intranasally.
  
  
  RESULTS
  The brains of Tg2576 mice and the temporal cortex of human AD brains had increased levels of miR-206. This miRNA targeted BDNF transcripts, and AM206 prevented the detrimental effects of amyloid-β42 on BDNF and dendritic spine degeneration in Tg2576 neurons. Injection of AM206 into the cerebral ventricles of AD mice increased the brain levels of BDNF and improved their memory function. In parallel, AM206 enhanced the hippocampal synaptic density and neurogenesis. Furthermore, intranasally administered AM206 also reached the brain and increased BDNF levels and memory function in AD mice.
  
  
  CONCLUSIONS
  Our findings demonstrate a novel miRNA-dependent regulation of BDNF in AD and suggest possible therapeutic approaches, such as noninvasive intranasal delivery of AM206.
authors.affiliation: Department of Neurology, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Soon-Tae
authors.initials: ST
authors.lastname: Lee
authors.forename: Kon
authors.initials: K
authors.lastname: Chu
authors.forename: Keun-Hwa
authors.initials: KH
authors.lastname: Jung
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Huh
authors.forename: Hyejin
authors.initials: H
authors.lastname: Yoon
authors.forename: Dong-Kyu
authors.initials: DK
authors.lastname: Park
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Lim
authors.forename: Jeong-Min
authors.initials: JM
authors.lastname: Kim
authors.forename: Daejong
authors.initials: D
authors.lastname: Jeon
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.forename: Sang Kun
authors.initials: SK
authors.lastname: Lee
authors.forename: Manho
authors.initials: M
authors.lastname: Kim
authors.forename: Jae-Kyu
authors.initials: JK
authors.lastname: Roh
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001596:Benzylamines / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D005239:Fear / Q000187:drug effects / Q000523:psychology; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007858:Learning / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D046228:Microarray Analysis; D055495:Neurogenesis / Q000187:drug effects; D009525:Niacin / Q000031:analogs & derivatives / Q000627:therapeutic use; D020319:Oligodeoxyribonucleotides, Antisense / Q000627:therapeutic use; D018709:Statistics, Nonparametric; D016708:Synaptophysin / Q000378:metabolism
chemical_list: C548543:(5-(2-((benzoyloxycarbonylethylamino)methyl)-4-trifluoromethylphenyl)pyridin-3-yl)acetic acid; D001596:Benzylamines; D019208:Brain-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; C546087:MIRN206 microRNA, human; D035683:MicroRNAs; D020319:Oligodeoxyribonucleotides, Antisense; D016708:Synaptophysin; D009525:Niacin