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Walter J Lukiw, Surjyadipta Bhattacharjee, Peter Alexandrov, Brandon Jones, James M Hill, Yuhai Zhao, Prerna Dua; Regulation of the innate-immune response glycoprotein complement factor H (CFH; chr1q32) in age-related macular degeneration (AMD) and sporadic Alzheimer’s disease (AD) by a novel NF-kB-sensitive, miRNA-146a- and miRNA-155-mediated genetic switch. Invest. Ophthalmol. Vis. Sci. 2014;55(13):626.
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Progressive degeneration of the neocortex and retina are associated with aberrant innate-immune signaling and inflammatory degeneration in age-related macular degeneration (AMD) and Alzheimer’s disease (AD). One pivotal player in this pathogenic system is complement factor H (CFH), found to be significantly reduced in abundance in AMD and AD. In these studies we investigated (1) the mechanism of CFH expression regulation in AMD and AD involving the up-regulated, NF-kB-sensitive miRNA-146a and miRNA-155, and (2) the effects of anti-NF-kB and anti-miRNA therapeutic strategies useful for the clinical management of these common disorders.
Aβ42-peptide- and/or TNFα-induced stress; AMD and AD tissues; bioinformatics; DNA array and RNA sequencing; human retinal and brain cells; LED-Northern dot blot analysis; micro-RNA array; NF-kB-inhibitors CAY10512, curcumin, CAPE; RT-PCR; CFH-luciferase-reporter transfection; Western analysis.
A ~4200 nucleotide (nt) CFH mRNA of the human brain and retina included a 232 nt 3’-UTR, containing recognition features for 27 potential miRNA interactions. Based on energy of association, tissue-selective miRNA abundance and RNA sequencing a 37 nt miRNA internal control region (ICR) was further identified that consisted of overlapping binding sites for miRNA-146a and miRNA-155. Binding of either miRNA-146a or miRNA-155 to the CFH 3'UTR ICR dramatically decreased CFH expression in brain and retinal cells. This deficit was reversed using specific NF-kB inhibitors and anti-miRNA strategies.
Our perception on the mechanism and relevance of miRNA signaling in brain and retina continues to evolve. For the first time these data provide evidence for a novel miRNA-mediated genetic switch in the CFH mRNA 3’-UTR used differentially in the brain and retina. We also show for the first time a synergistic effect of 2 NF-kB-sensitive miRNAs in the regulation of CFH expression. These data further suggest that epigenetic mechanisms involving inducible miRNAs contribute to immune deficits and inflammatory degeneration characteristic of progressive, age-related disorders, and further support the use of novel transcription factor- and nucleic acid-based therapeutic strategies in the clinical management of AMD and AD.
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