Fluvoxamine maleate ameliorates Alzheimer disease pathology by mitigating amyloid-beta load and neuroinflammation in 5XFAD mice

Abstract

BackgroundAlzheimer pathology (AD) is accompanied by the deposition of amyloid beta (A{beta}) and chronic neuroinflammation, where NLRP3 inflammasome is particularly involved. In this study, we found that the OCD drug fluvoxamine maleate (FXN) can potently ameliorate AD pathology in 5XFAD mice by autophagy-mediated clearance of A{beta} and inhibition of NLRP3 inflammasome. MethodsWe used mice primary astrocytes to establish the mechanism of action of FXN against NLRP3 inflammasome by using various techniques like ELISA, Western blotting, confocal microscopy, Immunofluorescence, etc. The validation of the anti-AD activity of FXN was done in transgenic 5XFAD mice after two months of treatment followed by behavior analysis and studying inflammatory and autophagy proteins along with immunohistochemistry analysis for A{beta} load in the hippocampi. ResultsOur data showed that FXN induces autophagy to inhibit NF-{kappa}B and NLRP3 inflammasome at a low concentration of 78 nM apart from directly inhibiting NLRP3 inflammasome in primary astrocytes. FXN activated the PRKAA2 pathway through CAMKK2 signaling, which led to the induction of autophagy in primary astrocytes. FXN inhibited the ATP-mediated NLRP3 inflammasome through autophagic degradation of NF-{kappa}B and thus caused the downregulation of pro-IL-1{beta} and NLRP3. The anti-NLRP3 inflammasome effect of FXN was reversed when autophagy was inhibited either by genetic knockdown of the PRKAA2 pathway or by bafilomycin A1. Furthermore, FXN treatment led to improved AD pathology in 5XFAD mice, which displayed a significant improvement in multiple behavior parameters like working memory and neuromuscular coordination and they behaved more like wild-type animals. We found that FXN improved behavior in 5XFAD mice by clearing the A{beta} deposits from the hippocampi along with a significant reduction in multiple inflammatory proteins, including NF-{kappa}B, GFAP, IBA1, IL-1{beta}, TNF-, and IL-6 associated with NF-{kappa}B and NLRP3 inflammasome in the brain. Moreover, these changes were accompanied by increased expression of autophagic proteins. ConclusionOur data suggest that to ameliorate AD pathology, FXN simultaneously targets two key pathological features of AD that is A{beta} deposits and neuroinflammation. Being an approved drug, FXN can be pushed as a potential drug candidate for human studies against AD.