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J Biol Chem. 2008 Nov 14;283(46):31315-22. doi: 10.1074/jbc.M805371200. Epub 2008 Sep 18.

An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells.

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  • 1Louisiana State University Neuroscience Center, Louisiana State University Health Science Center, New Orleans, Louisiana 70112-2272, USA. wlukiw@lsuhsc.edu

Abstract

Human brains retain discrete populations of micro RNA (miRNA) species that support homeostatic brain gene expression functions; however, specific miRNA abundance is significantly altered in neurological disorders such as Alzheimer disease (AD) when compared with age-matched controls. Here we provide evidence in AD brains of a specific up-regulation of an NF-kappaB-sensitive miRNA-146a highly complementary to the 3'-untranslated region of complement factor H (CFH), an important repressor of the inflammatory response of the brain. Up-regulation of miRNA-146a coupled to down-regulation of CFH was observed in AD brain and in interleukin-1beta, Abeta42, and/or oxidatively stressed human neural (HN) cells in primary culture. Transfection of HN cells using an NF-kappaB-containing pre-miRNA-146a promoter-luciferase reporter construct in stressed HN cells showed significant up-regulation of luciferase activity that paralleled decreases in CFH gene expression. Treatment of stressed HN cells with the NF-kappaB inhibitor pyrollidine dithiocarbamate or the resveratrol analog CAY10512 abrogated this response. Incubation of an antisense oligonucleotide to miRNA-146a (anti-miRNA-146a; AM-146a) was found to restore CFH expression levels. These data indicate that NF-kappaB-sensitive miRNA-146a-mediated modulation of CFH gene expression may in part regulate an inflammatory response in AD brain and in stressed HN cell models of AD and illustrate the potential for anti-miRNAs as an effective therapeutic strategy against pathogenic inflammatory signaling.

PMID:
18801740
[PubMed - indexed for MEDLINE]
PMCID:
PMC2581572
Free PMC Article
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