title: Dipeptidyl Vinyl Sulfone as a Novel Chemical Tool to Inhibit HMGB1/NLRP3-Inflammasome and Inflamma-miRs in Aβ-Mediated Microglial Inflammation.
abstract: Rapid microglial activation and associated inflammatory pathways contribute to immune-defense and tissue repair in the central nervous system (CNS). However, persistent activation of these cells will ultimately result in vast production of pro-inflammatory mediators and other neurotoxic factors, which may induce neuronal damage and contribute to chronic neurodegenerative diseases, as Alzheimer's disease (AD). Therefore, small molecules with immunomodulatory effects on microglia may be considered as potential tools to counteract their proinflammatory phenotype and neuroimmune dysregulation in such disorders. Indeed, reducing amyloid-β (Aβ)-induced microglia activation is believed to be effective in treating AD. In this study, we investigated whether dipeptidyl vinyl sulfone (VS) was able to attenuate Aβ-mediated inflammatory response using a mouse microglial (N9) cell line and a solution containing a mixture of Aβ aggregates. We show that low levels of VS are able to prevent cell death while reducing microglia phagocytosis upon Aβ treatment. VS also suppressed Aβ-induced expression of inflammatory mediators in microglia, such as matrix metalloproteinase (MMP)-2 and MMP-9, as well as high-mobility group box protein-1 (HMGB1), nod-like receptor protein 3 (NLRP3)-inflammasome, and interleukin (IL)-1β. Interestingly, increased expression of the two critical inflammation-related microRNAs (miR)-155 and miR-146a in microglia upon Aβ treatment was also prevented by VS coincubation. Taken together, VS emerges as a potential new therapeutic strategy worthy of further investigation in improved cellular and animal models of AD.
authors: Neuron Glia Biology in Health and Disease Group, Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Medicinal Chemistry Group, Research Institute for Medicines (iMed.ULisboa), and ∥Department of Pharmaceutical Chemistry and Therapeutics, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Ana S
authors: AS
authors: Falcão
authors: Neuron Glia Biology in Health and Disease Group, Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Medicinal Chemistry Group, Research Institute for Medicines (iMed.ULisboa), and ∥Department of Pharmaceutical Chemistry and Therapeutics, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Luís A R
authors: LA
authors: Carvalho
authors: Neuron Glia Biology in Health and Disease Group, Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Medicinal Chemistry Group, Research Institute for Medicines (iMed.ULisboa), and ∥Department of Pharmaceutical Chemistry and Therapeutics, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Gonçalo
authors: G
authors: Lidónio
authors: Neuron Glia Biology in Health and Disease Group, Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Medicinal Chemistry Group, Research Institute for Medicines (iMed.ULisboa), and ∥Department of Pharmaceutical Chemistry and Therapeutics, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Ana R
authors: AR
authors: Vaz
authors: Neuron Glia Biology in Health and Disease Group, Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Medicinal Chemistry Group, Research Institute for Medicines (iMed.ULisboa), and ∥Department of Pharmaceutical Chemistry and Therapeutics, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Susana D
authors: SD
authors: Lucas
authors: Neuron Glia Biology in Health and Disease Group, Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Medicinal Chemistry Group, Research Institute for Medicines (iMed.ULisboa), and ∥Department of Pharmaceutical Chemistry and Therapeutics, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Rui
authors: R
authors: Moreira
authors: Neuron Glia Biology in Health and Disease Group, Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Medicinal Chemistry Group, Research Institute for Medicines (iMed.ULisboa), and ∥Department of Pharmaceutical Chemistry and Therapeutics, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Dora
authors: D
authors: Brites
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000187:drug effects*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D010586:Phagocytes / Q000187:drug effects; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D024243:HMGB1 Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; C532623:Mirn155 microRNA, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010446:Peptide Fragments; D013450:Sulfones; C075222:amyloid beta-protein (1-42); C009873:divinyl sulfone; D020782:Matrix Metalloproteinases
keywords: HMGB1; Microglia; amyloid-β peptide; inflammasome; microRNAs; vinyl sulfones