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Walter J Lukiw, Surjyadipta Bhattacharjee, Yuhai Zhao, Maire E Percy, Evgeny I. Rogaev, Prerna Sethi-Dua; miRNA-34a down-regulates the triggering receptor and phagocytosis sensor TREM2 in age-related macular degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3989.
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© ARVO (1962-2015); The Authors (2016-present)
Pathogenic aggregation of Aβ42-peptides & drusen formation in AMD is due in part to the inability of phagocytic mechanisms to clear neurotoxic & self-aggregating Aβ42-peptides from the extracellular space. One key participant in Aβ42 clearance is the triggering receptor expressed in microglial cells-2 (TREM2), a transmembrane sensor-receptor of the immune-globulin gene superfamily. Here we have examined microRNA (miRNA)-mediated amyloid peptide clearance mechanisms involving TREM2 in aging 5xFAD retina, in AMD & in Aβ42-peptide- or cytokine-stressed microglial cells.
Aβ42 analysis, bioinformatics, DNA & miRNA arrays, ELISA, microglial culture, Northern & Western immunocytochemistry, RNA sequencing, RT-PCR, transfection
Parallel DNA & miRNA array, RT-PCR, Northern & Western analysis indicated up-regulation of an NF-кB-sensitive miRNA-34a & down-regulation of TREM2 in the same samples. Aging 5xFAD mice exhibited progressive decreases in retinal TREM2; transfection using luciferase reporters showed that miRNA-34a targets the TREM2 mRNA 3’UTR to down-regulate TREM2 expression. C8B4 microglial cells challenged with Aβ42 were able to phagocytose these neurotoxic peptides, while miRNA-34a down-regulated both TREM2 abundance and the ability of microglial cells to phagocytose. Treatment of stressed microglial cells with the NF-kB inhibitor/resveratrol analog CAY10512, the anti-inflammatory caffeic-acid phenethyl ester (CAPE) or the natural phenolic antioxidant diferuloylmethane (curcumin) abrogated these responses; anti-miRNA-34a strategies were found to normalize induced miRNA-34a levels & restore homeostatic TREM2 expression.
<br /> For the first time we report a miRNA-34a-mediated down-regulation of TREM2 in AMD, in aging 5xFAD retina & in stressed microglia. Our data support 4 novel observations: (i) that a NF-kB-sensitive, miRNA-34a-mediated modulation of TREM2 regulates a phagocytic response; (ii) that gene products encoded on 2 different chromosomes (TREM2 at chr6p21.1 and miRNA-34a at chr1q36.22) orchestrate an Aβ42-clearance system in the retina; (iii) that this NF-kB-miRNA-34a-TREM2 system is inducible & effectively clears Aβ42 peptide monomers from the extracellular medium; & (iv) that these results underscore the potential for anti-NF-kB/anti-miRNA-based therapeutic strategies against deficits in phagocytic signaling that drive amyloidogenesis.
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