April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
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
Author Affiliations & Notes
  • Walter J Lukiw
    Neuroscience & Ophthalmology, Lousiana State Univ Hlth Sci Ctr, New Orleans, LA
    Neurogenetics, Russian Academy of Medical Sciences, Moscow, Russian Federation
  • Surjyadipta Bhattacharjee
    Neuroscience & Ophthalmology, Lousiana State Univ Hlth Sci Ctr, New Orleans, LA
  • Peter Alexandrov
    Neurogenetics, Russian Academy of Medical Sciences, Moscow, Russian Federation
  • Brandon Jones
    Neuroscience & Ophthalmology, Lousiana State Univ Hlth Sci Ctr, New Orleans, LA
  • James M Hill
    Neuroscience & Ophthalmology, Lousiana State Univ Hlth Sci Ctr, New Orleans, LA
    Departments of Microbiology and Pharmacology, Louisiana State University Health Science Center, New Orleans, LA
  • Yuhai Zhao
    Neuroscience & Ophthalmology, Lousiana State Univ Hlth Sci Ctr, New Orleans, LA
    Center for Translational Injury Research, University of Texas Health Sciences Center, Houston, TX
  • Prerna Dua
    Health Information Management, Louisiana Technical University, Ruston, LA, LA
  • Footnotes
    Commercial Relationships Walter Lukiw, None; Surjyadipta Bhattacharjee, None; Peter Alexandrov, None; Brandon Jones, None; James Hill, None; Yuhai Zhao, None; Prerna Dua, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 626. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: 412 age-related macular degeneration • 533 gene/expression • 413 aging  
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