An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells.
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.
Lukiw
Walter J
WJ
Louisiana State University Neuroscience Center, Louisiana State University Health Science Center, New Orleans, Louisiana 70112-2272, USA. wlukiw@lsuhsc.edu
Zhao
Yuhai
Y
Cui
Jian Guo
JG
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D017242:Complement Factor H / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D017930:Genes, Reporter; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D012680:Sensitivity and Specificity; D013312:Stress, Physiological; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D016229:Amyloid beta-Peptides; D018836:Inflammation Mediators; D035683:MicroRNAs; D016328:NF-kappa B; D010446:Peptide Fragments; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42); D017242:Complement Factor H; D006861:Hydrogen Peroxide
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