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 researchers at the LSU Neuroscience Center 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.

miRNA was analyzed in an AD group (n = 23) and an age-matched control group (n = 23) using commercially available miRNA arrays from LC Sciences. 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.

 

 

miRNA-146a up-regulation in AD brain. A, merge of cy3/cy5 signals from a human micro-RNA panel (LC Sciences) indicates specific up-regulation of miRNA-146a (position A6; arrow). Levels of miRNA-9 (position A4), miRNA-132 (position A9), or miRNA-185 (position B6) showed no such changes (complete miRNA grid pattern available from LC Sciences). B, nylon membrane-bound DNA equivalents (10 μm) of three brain-enriched miRNAs and 5SRNA were probed with total 32P-radiolabeled miRNA fractions isolated from control or AD affected hippocampal CA1; representative Northern hybridization of select brain-enriched miRNAs reconfirmed up-regulation of miR-146a (arrows). Position A1, miRNA-9; A2, miRNA-132; B1, miRNA-146a; B2, 5SRNA. C, signals were quantified against internal 5SRNA levels in bar graph format. Data analysis of 23 control (CON) and 23 Alzheimer (ALZ) brains show a 3.3-fold increase of miRNA-146a expression in the neocortex (nctx) and a 2.3-fold increase in the hippocampus (hipp) over age-matched controls. *, significance over control p < 0.01 (ANOVA).

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Reference

Zhao Y, Lukiw WJ. (2008) An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem 283(46), 31315-22. [article]


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