| MicroRNA-153 physiologically inhibits expression of amyloid-β precursor protein in cultured human fetal brain cells and is dysregulated in a subset of Alzheimer disease patients. | |
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MedLine Citation:
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PMID: 22733824 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Regulation of amyloid-β (Aβ) precursor protein (APP) expression is complex. MicroRNAs (miRNAs) are expected to participate in the molecular network that controls this process. The composition of this network is, however, still undefined. Elucidating the complement of miRNAs that regulate APP expression should reveal novel drug targets capable of modulating Aβ production in AD. Here, we investigated the contribution of miR-153 to this regulatory network. A miR-153 target site within the APP 3'-untranslated region (3'-UTR) was predicted by several bioinformatic algorithms. We found that miR-153 significantly reduced reporter expression when co-transfected with an APP 3'-UTR reporter construct. Mutation of the predicted miR-153 target site eliminated this reporter response. miR-153 delivery in both HeLa cells and primary human fetal brain cultures significantly reduced APP expression. Delivery of a miR-153 antisense inhibitor to human fetal brain cultures significantly elevated APP expression. miR-153 delivery also reduced expression of the APP paralog APLP2. High functional redundancy between APP and APLP2 suggests that miR-153 may target biological pathways in which they both function. Interestingly, in a subset of human AD brain specimens with moderate AD pathology, miR-153 levels were reduced. This same subset also exhibited elevated APP levels relative to control specimens. Therefore, endogenous miR-153 inhibits expression of APP in human neurons by specifically interacting with the APP 3'-UTR. This regulatory interaction may have relevance to AD etiology, where low miR-153 levels may drive increased APP expression in a subset of AD patients. |
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Authors:
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Justin M Long; Balmiki Ray; Debomoy K Lahiri |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-06-25 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 287 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2012 Sep |
Date Detail:
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Created Date: 2012-09-10 Completed Date: 2012-11-19 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 31298-310 Citation Subset: IM |
Affiliation:
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Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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3' Untranslated Regions
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genetics Alzheimer Disease / genetics, metabolism*, pathology Amyloid beta-Protein Precursor / biosynthesis*, genetics Brain / metabolism*, pathology Female Fetus / metabolism*, pathology Gene Expression Regulation* HeLa Cells Humans Male MicroRNAs / genetics, metabolism* Nerve Tissue Proteins / biosynthesis*, genetics |
| Grant Support | |
ID/Acronym/Agency:
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AG18379/AG/NIA NIH HHS; AG18884/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/3' Untranslated Regions; 0/APP protein, human; 0/Amyloid beta-Protein Precursor; 0/MIRN153 microRNA, human; 0/MicroRNAs; 0/Nerve Tissue Proteins |
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