title: microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration.
abstract: The aggregation of Aβ42-peptides and the formation of drusen in age-related macular degeneration (AMD) are due in part to the inability of homeostatic phagocytic mechanisms to clear self-aggregating Aβ42-peptides from the extracellular space. The triggering receptor expressed in myeloid/microglial cells-2 (TREM2), a trans-membrane-spanning, sensor-receptor of the immune-globulin/lectin-like gene superfamily is a critical component of Aβ42-peptide clearance. Here we report a significant deficit in TREM2 in AMD retina and in cytokine- or oxidatively-stressed microglial (MG) cells. RT-PCR, miRNA-array, LED-Northern and Western blot studies indicated up-regulation of a microglial-enriched NF-кB-sensitive miRNA-34a coupled to a down-regulation of TREM2 in the same samples. Bioinformatics/transfection-luciferase reporter assays indicated that miRNA-34a targets the 299 nucleotide TREM2-mRNA-3'UTR, resulting in TREM2 down-regulation. C8B4-microglial cells challenged with Aβ42 were able to phagocytose these peptides, while miRNA-34a down-regulated both TREM2 and the ability of microglial-cells to phagocytose. Treatment of TNFα-stressed MG cells with phenyl-butyl nitrone (PBN), caffeic-acid phenethyl ester (CAPE), the NF-kB - [corrected] inhibitor/resveratrol analog CAY10512 or curcumin abrogated these responses. Incubation of anti-miRNA-34a (AM-34a) normalized miRNA-34a abundance and restored TREM2 back to homeostatic levels. These data support five novel observations: (i) that a ROS- and NF-kB - [corrected] sensitive, miRNA-34a-mediated modulation of TREM2 may in part regulate the phagocytic response; (ii) that gene products encoded on two different chromosomes (miRNA-34a at chr1q36.22 and TREM2 at chr6p21.1) orchestrate a phagocytic-Aβ42-peptide clearance-system; (iii) that this NF-kB-mediated-miRNA-34a-TREM2 mechanism is inducible from outside of the cell; (iv) that when operating normally, this pathway can clear Aβ42 peptide monomers from the extracellular medium; and (v) that anti-NF-kB and/or anti-miRNA (AM)-based therapeutic strategies may be useful against deficits in TREM-2 receptor-based-sensing and -phagocytic signaling that promote pathogenic amyloidogenesis.
authors.affiliation: LSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA, 70112, United States of America.
authors.forename: Surjyadipta
authors.initials: S
authors.lastname: Bhattacharjee
authors.affiliation: LSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA, 70112, United States of America.|Department of Anatomy and Cell Biology, Louisiana State University Health Science Center, New Orleans, LA, 70112, United States of America.
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Louisiana State Technical University, Ruston, LA, 71270, United States of America.
authors.forename: Prerna
authors.initials: P
authors.lastname: Dua
authors.affiliation: Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA, 01604, United States of America.|Department of Genomics and Human Genetics, Laboratory of Evolutionary Genomics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991, Russia.|Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119234, Russia.
authors.forename: Evgeny I
authors.initials: EI
authors.lastname: Rogaev
authors.affiliation: LSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA, 70112, United States of America.|Department of Genomics and Human Genetics, Laboratory of Evolutionary Genomics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991, Russia.|Department of Ophthalmology, Louisiana State University Health Science Center, New Orleans, LA, 70112, United States of America.|Department of Neurology, Louisiana State University Health Science Center, New Orleans, LA, 70112, United States of America.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Lukiw
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D019295:Computational Biology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D018384:Oxidative Stress / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D020413:3' Untranslated Regions; D053583:Interleukin-1beta; C522425:MIRN34 microRNA, human; D008562:Membrane Glycoproteins; D035683:MicroRNAs; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide