Статья

De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease

Hon Kit WongCenter for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA 02115, USATatyana Veremeyko1Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA 02115, USA,Nehal Patel2Harvard NeuroDiscovery Center, Massachusetts General Hospital and Harvard Medical School, Building 114, Charlestown, MA 02129, USA,Cynthia A. Lemere1Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA 02115, USA,Dominic M. Walsh3Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, MA, USA andChristine Esau4Regulus Therapeutics, 3545 John Hopkins Ct., San Diego, CA 92121, USACharles Vanderburg2Harvard NeuroDiscovery Center, Massachusetts General Hospital and Harvard Medical School, Building 114, Charlestown, MA 02129, USA,Anna M. Krichevsky1Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA 02115, USA,

2013en

ABI

Аннотация

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.

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Идентификаторы

DOI: 10.1093/hmg/ddt164

Цитирования и источники

Цитирований: 2Использованных источников: 0

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