An NF-κB-sensitive micro RNA-146a-mediated inflammatory circuit in alzheimer disease and in stressed human brain cells

Walter J. Lukiw, Yuhai Zhao, Guo Cui Jian

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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-κB-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-1β, Aβ42, and/or oxidatively stressed human neural (HN) cells in primary culture. Transfection of HN cells using an NF-κB-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-κB 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-κB-sensitive miRNA-146a-mediated modulation of CFH gene expressionmayin part regulate an inflammatory response inAD 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.

Original languageEnglish (US)
Pages (from-to)31315-31322
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number46
DOIs
StatePublished - Nov 14 2008

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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