Document Detail


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.
MedLine Citation:
PMID:  22733824     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Justin M Long; Balmiki Ray; Debomoy K Lahiri
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-25
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-10     Completed Date:  2012-11-19     Revised Date:  2013-09-10    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  31298-310     Citation Subset:  IM    
Affiliation:
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
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MeSH Terms
Descriptor/Qualifier:
3' Untranslated Regions / 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:
AG18379/AG/NIA NIH HHS; AG18884/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/3' Untranslated Regions; 0/APP protein, human; 0/Amyloid beta-Protein Precursor; 0/MIRN153 microRNA, human; 0/MicroRNAs; 0/Nerve Tissue Proteins
Comments/Corrections

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