title: De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a multifactorial and fatal neurodegenerative disorder for which the mechanisms leading to profound neuronal loss are incompletely recognized. MicroRNAs (miRNAs) are recently discovered small regulatory RNA molecules that repress gene expression and are increasingly acknowledged as prime regulators involved in human brain pathologies. Here we identified two homologous miRNAs, miR-132 and miR-212, downregulated in temporal cortical areas and CA1 hippocampal neurons of human AD brains. Sequence-specific inhibition of miR-132 and miR-212 induces apoptosis in cultured primary neurons, whereas their overexpression is neuroprotective against oxidative stress. Using primary neurons and PC12 cells, we demonstrate that miR-132/212 controls cell survival by direct regulation of PTEN, FOXO3a and P300, which are all key elements of AKT signaling pathway. Silencing of these three target genes by RNAi abrogates apoptosis caused by the miR-132/212 inhibition. We further demonstrate that mRNA and protein levels of PTEN, FOXO3a, P300 and most of the direct pro-apoptotic transcriptional targets of FOXO3a are significantly elevated in human AD brains. These results indicate that the miR-132/miR-212/PTEN/FOXO3a signaling pathway contributes to AD neurodegeneration.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA 02115, USA.
authors.forename: Hon-Kit Andus
authors.initials: HK
authors.lastname: Wong
authors.forename: Tatiana
authors.initials: T
authors.lastname: Veremeyko
authors.forename: Nehal
authors.initials: N
authors.lastname: Patel
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Lemere
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.forename: Christine
authors.initials: C
authors.lastname: Esau
authors.forename: Charles
authors.initials: C
authors.lastname: Vanderburg
authors.forename: Anna M
authors.initials: AM
authors.lastname: Krichevsky
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C547077:MIRN132 microRNA, human; C551411:MIRN212 microRNA, human; D035683:MicroRNAs; D006861:Hydrogen Peroxide; D050880:p300-CBP Transcription Factors; D051059:PTEN Phosphohydrolase