ABSTRACT
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+Aß-induced caspase 1 activation in microglia and this was accompanied by IL-1ß 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 Aß phagocytosis in vitro, and it reduced Aß 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.
Subject(s)
Amyloid beta-Peptides/metabolism , Cognition/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Inflammasomes/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Sulfones/pharmacology , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Disease Models, Animal , Furans , Indenes , Inflammasomes/metabolism , Mice , Microglia/drug effects , Microglia/metabolism , Presenilin-1/genetics , Presenilin-1/metabolism , SulfonamidesABSTRACT
The active form of vitamin D has effects on both innate and adaptive immune responses that may influence the outcome in many infectious diseases. Observational studies conclusively show that a low vitamin D status is associated with an increased occurrence of respiratory viral infections, which globally represent significant health and financial burdens. However, no consistent protective effects are evident in prospective clinical trials carried out to date where vitamin D was provided as a dietary supplement, except possibly in cases where the starting vitamin D status of the individual was considered deficient. Thus far, vitamin D has not been found to enhance the immune response to vaccines. The design of future prospective clinical trials assessing a role for vitamin D in respiratory viral infections requires very careful planning to avoid the uncertainties associated with the data available currently.
