Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice.

Autor: Dempsey C; Trinity College Institute for Neuroscience, Trinity College, Dublin 2, Ireland., Rubio Araiz A; Trinity College Institute for Neuroscience, Trinity College, Dublin 2, Ireland., Bryson KJ; Trinity College Institute for Neuroscience, Trinity College, Dublin 2, Ireland., Finucane O; Trinity College Institute for Neuroscience, Trinity College, Dublin 2, Ireland., Larkin C; Trinity College Institute for Neuroscience, Trinity College, Dublin 2, Ireland., Mills EL; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland., Robertson AAB; Institute for Molecular Bioscience, The University of Queensland, Australia., Cooper MA; Institute for Molecular Bioscience, The University of Queensland, Australia., O'Neill LAJ; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland., Lynch MA; Trinity College Institute for Neuroscience, Trinity College, Dublin 2, Ireland. Electronic address: lynchma@tcd.ie.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2017 Mar; Vol. 61, pp. 306-316. Date of Electronic Publication: 2016 Dec 18.
DOI: 10.1016/j.bbi.2016.12.014
Abstrakt: Activation of the inflammasome is implicated in the pathogenesis of an increasing number of inflammatory diseases, including Alzheimer's disease (AD). Research reporting inflammatory changes in post mortem brain tissue of individuals with AD and GWAS data have convincingly demonstrated that neuroinflammation is likely to be a key driver of the disease. This, together with the evidence that genetic variants in the NLRP3 gene impact on the risk of developing late-onset AD, indicates that targetting inflammation offers a therapeutic opportunity. Here, we examined the effect of the small molecule inhibitor of the NLRP3 inflammasome, MCC950, on microglia in vitro and in vivo. The findings indicate that MCC950 inhibited LPS+Aβ-induced caspase 1 activation in microglia and this was accompanied by IL-1β release, without inducing pyroptosis. We demonstrate that MCC950 also inhibited inflammasome activation and microglial activation in the APP/PS1 mouse model of AD. Furthermore, MCC950 stimulated Aβ phagocytosis in vitro, and it reduced Aβ accumulation in APP/PS1 mice, which was associated with improved cognitive function. These data suggest that activation of the inflammasome contributes to amyloid accumulation and to the deterioration of neuronal function in APP/PS1 mice and demonstrate that blocking assembly of the inflammasome may prove to be a valuable strategy for attenuating changes that negatively impact on neuronal function.
(Copyright © 2016 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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