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Walter Lukiw, Brandon Jones, Surjyadipta Bhattacharjee, Peter Alexandrov, Prerna Dua, Yuahi Zhao; TREM2 (chr6p21.1) and CFH (chr1q32) regulation by NF-kB-sensitive miRNAs in age-related macular degeneration (AMD) and Alzheimer's disease (AD). Invest. Ophthalmol. Vis. Sci. 2013;54(15):3652.
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Age-related macular degeneration (AMD) and Alzheimer’s disease (AD), progressive degenerations of layered multicellular assemblies in the retina and neocortex, are both associated with altered innate-immune responses, amyloidogenesis and progressive neurodegeneration. Very recently, loss-of-function for the triggering receptor expressed in myeloid and microglial cells 2 (TREM2; chr6p21.1), have been associated with inflammatory neurodegeneration in AD. The pathological role of TREM2 appears to be related to aberrant complement factor H (CFH; chr 1q32) signaling functions in both AMD and AD. The purpose of these studies was to examine the epigenetic regulation of TREM2 and CFH in AMD and AD, and the up-regulated micro RNAs (miRNAs) which regulate their expression.
3’-untranslated region (3’-UTR) sequence and vector analysis; Aβ42-peptide+TNFα-induced and/or hydrogen peroxide-induced stress; bioinformatics; CAPE, CAY10512, DNA array; DNA sequencing; human brain postmortem tissue; human retinal tissue; human retinal and brain cells in primary culture; gel shift assay; LED-Northern micro-dot blot analysis; micro-RNA array; protected anti-miRNAs; RT-PCR; TREM-2- and CFH-3’-UTR-luciferase-reporter transfection assay; Western immuno-histochemistry
In AMD retina, in AD brain and in stressed primary human brain and retinal cells we identified small families of NF-kB-regulated miRNAs that include miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. Each of the promoters that regulate transcription of the precursors for these 5 miRNAs contain functional NF-kB binding domains. Inducible combinations of these mature miRNAs target the TREM2 mRNA-3’-UTR and/or the CFH mRNA-3’-UTR, resulting in significant decreases in TREM2 or CFH expression (p<0.01, ANOVA). Both NF-kB and anti-miRNA (AM) strategies were found to significantly restore TREM2 and CFH expression back to near homeostatic levels.
These data provide evidence for common underlying miRNA-mediated pathogenic mechanisms in retinal and brain neurodegenerative disease, and for the first time implicate TREM2-involvement in AMD. Epigenetic mechanisms involving inducible miRNAs contribute to inflammatory degeneration characteristic of both AMD and AD, and suggest novel therapeutic treatment strategies in the clinical management of these progressive, age-related disorders.
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