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De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease.
Hum Mol Genet. 2013 Aug 01; 22(15):3077-92.HM

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.

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Authors+Show Affiliations

Wong HK
Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA 02115, USA.
Veremeyko T
No affiliation info available
Patel N
No affiliation info available
Lemere CA
No affiliation info available
Walsh DM
No affiliation info available
Esau C
No affiliation info available
Vanderburg C
No affiliation info available
Krichevsky AM
No affiliation info available

MeSH

Alzheimer DiseaseAnimalsApoptosisBrainDown-RegulationForkhead Box Protein O3Forkhead Transcription FactorsGene Expression RegulationHumansHydrogen PeroxideMiceMicroRNAsModels, BiologicalNeuronsPTEN PhosphohydrolaseRNA InterferenceRatsSignal Transductionp300-CBP Transcription Factors

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23585551

Citation

Wong, Hon-Kit Andus, et al. "De-repression of FOXO3a Death Axis By microRNA-132 and -212 Causes Neuronal Apoptosis in Alzheimer's Disease." Human Molecular Genetics, vol. 22, no. 15, 2013, pp. 3077-92.
Wong HK, Veremeyko T, Patel N, et al. De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease. Hum Mol Genet. 2013;22(15):3077-92.
Wong, H. K., Veremeyko, T., Patel, N., Lemere, C. A., Walsh, D. M., Esau, C., Vanderburg, C., & Krichevsky, A. M. (2013). De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease. Human Molecular Genetics, 22(15), 3077-92. https://doi.org/10.1093/hmg/ddt164
Wong HK, et al. De-repression of FOXO3a Death Axis By microRNA-132 and -212 Causes Neuronal Apoptosis in Alzheimer's Disease. Hum Mol Genet. 2013 Aug 1;22(15):3077-92. PubMed PMID: 23585551.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease. AU - Wong,Hon-Kit Andus, AU - Veremeyko,Tatiana, AU - Patel,Nehal, AU - Lemere,Cynthia A, AU - Walsh,Dominic M, AU - Esau,Christine, AU - Vanderburg,Charles, AU - Krichevsky,Anna M, Y1 - 2013/04/11/ PY - 2013/4/16/entrez PY - 2013/4/16/pubmed PY - 2014/2/1/medline SP - 3077 EP - 92 JF - Human molecular genetics JO - Hum Mol Genet VL - 22 IS - 15 N2 - 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. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/23585551/De_repression_of_FOXO3a_death_axis_by_microRNA_132_and__212_causes_neuronal_apoptosis_in_Alzheimer's_disease_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddt164 DB - PRIME DP - Unbound Medicine ER -