{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T13:42:37Z","timestamp":1793194957956,"version":"4.5.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T00:00:00Z","timestamp":1722211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Alzheimer pathology (AD) is characterized by the deposition of amyloid beta (A\u03b2) and chronic neuroinflammation, with the NLRP3 inflammasome playing a significant role. This study demonstrated that the OCD drug fluvoxamine maleate (FXN) can potently ameliorate AD pathology in 5XFAD mice by promoting autophagy-mediated clearance of A\u03b2 and inhibiting the NLRP3 inflammasome. <\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We 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 anti-AD activity of FXN was validated in transgenic 5XFAD mice following two months of treatment. This was followed by behavior analysis, examination of inflammatory and autophagy proteins and immunohistochemistry analysis for A\u03b2 load in the hippocampi.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our data showed that FXN, at a low concentration of 78 nM, induces autophagy to inhibit NF-\u03baB and the NLRP3 inflammasome, apart from directly inhibiting NLRP3 inflammasome in primary astrocytes. FXN activated the PRKAA2 pathway through CAMKK2 signaling, leading to autophagy induction. It inhibited the ATP-mediated NLRP3 inflammasome activation by promoting the autophagic degradation of NF-\u03baB, resulting in the downregulation of pro-IL-1\u03b2 and NLRP3. The anti-NLRP3 inflammasome effect of FXN was reversed when autophagy was inhibited by either genetic knockdown of the PRKAA2 pathway or pharmacological inhibition with bafilomycin A1. Furthermore, FXN treatment led to improved AD pathology in 5XFAD mice, resulting in significant improvements in various behavioral parameters such as working memory and neuromuscular coordination, making their behavior more similar to that of wild-type animals. FXN improved behavior in 5XFAD mice by clearing the A\u03b2 deposits from the hippocampi and significantly reducing multiple inflammatory proteins, including NF-\u03baB, GFAP, IBA1, IL-1\u03b2, TNF-\u03b1, and IL-6, which are associated with NF-\u03baB and NLRP3 inflammasome in the brain. Moreover, these changes were accompanied by increased expression of autophagic proteins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our data suggest that FXN ameliorates AD pathology, by simultaneously targeting two key pathological features: A\u03b2 deposits and neuroinflammation. As an already approved drug, FXN holds potential as a candidate for human studies against AD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1418422","type":"journal-article","created":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T04:39:56Z","timestamp":1722227996000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Fluvoxamine maleate alleviates amyloid-beta load and neuroinflammation in 5XFAD mice to ameliorate Alzheimer disease pathology"],"prefix":"10.3389","volume":"15","author":[{"given":"Sukhleen","family":"Kaur","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuhu","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankita","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamalpreet 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