title: Early miR-155 upregulation contributes to neuroinflammation in Alzheimer's disease triple transgenic mouse model.
abstract: MicroRNAs (miRNAs) have emerged as a class of small, endogenous, regulatory RNAs that exhibit the ability to epigenetically modulate the translation of mRNAs into proteins. This feature enables them to control cell phenotypes and, consequently, modify cell function in a disease context. The role of inflammatory miRNAs in Alzheimer's disease (AD) and their ability to modulate glia responses are now beginning to be explored. In this study, we propose to disclose the functional role of miR-155, one of the most well studied immune-related miRNAs in AD-associated neuroinflammatory events, employing the 3xTg AD animal model. A strong upregulation of miR-155 levels was observed in the brain of 12-month-old 3xTg AD animals. This event occurred simultaneously with an increase of microglia and astrocyte activation, and before the appearance of extracellular Aβ aggregates, suggesting that less complex Aβ species, such as Aβ oligomers may contribute to early neuroinflammation. In addition, we investigated the contribution of miR-155 and the c-Jun transcription factor to the molecular mechanisms that underlie Aβ-mediated activation of glial cells. Our results suggest early miR-155 and c-Jun upregulation in the 3xTg AD mice, as well as in Aβ-activated microglia and astrocytes, thus contributing to the production of inflammatory mediators such as IL-6 and IFN-β. This effect is associated with a miR-155-dependent decrease of suppressor of cytokine signaling 1. Furthermore, since c-Jun silencing decreases the levels of miR-155 in Aβ-activated microglia and astrocytes, we propose that miR-155 targeting can constitute an interesting and promising approach to control neuroinflammation in AD.
authors.affiliation: Doctoral Programme in Experimental Biology and Biomedicine, CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal, Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal, CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Joana R
authors.initials: JR
authors.lastname: Guedes
authors.affiliation: Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3001-401, Coimbra, Portugal.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Custódia
authors.affiliation: Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3001-401, Coimbra, Portugal.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Silva
authors.affiliation: Laboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal and CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Luís P
authors.initials: LP
authors.lastname: de Almeida
authors.affiliation: Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3001-401, Coimbra, Portugal, CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Pedroso de Lima
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal alcardoso@ci.uc.pt.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Cardoso
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D048031:JNK Mitogen-Activated Protein Kinases