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Hence, a multi-target drug would improve treatment efficacy. We applied a new multi-scale predictive modelling framework that integrates machine learning with biophysics and systems pharmacology to screen drugs for Alzheimer\u2019s disease using patients\u2019 tissue samples. Our predictive modelling framework identified ibudilast as a drug with repurposing potential to treat Alzheimer\u2019s disease. Ibudilast is a multi-target drug, as it is a phosphodiesterase inhibitor and toll-like receptor 4 (TLR4) antagonist. In addition, we predict that ibudilast inhibits off-target kinases (e.g. IRAK1 and GSG2). In Japan and other Asian countries, ibudilast is approved for treating asthma and stroke due to its anti-inflammatory potential.<\/jats:p>\n                  <jats:p>Based on these previous studies and on our predictions, we tested for the first time the efficacy of ibudilast in Fisher transgenic 344-AD rats. This transgenic rat model is unique as it exhibits hippocampal-dependent spatial learning and memory deficits and Alzheimer\u2019s disease pathology, including hippocampal amyloid plaques, tau paired-helical filaments, neuronal loss and microgliosis, in a progressive age-dependent manner that mimics the pathology observed in Alzheimer\u2019s disease patients. Following long-term treatment with ibudilast, transgenic rats were evaluated at 11 months of age for spatial memory performance and Alzheimer\u2019s disease pathology.<\/jats:p>\n                  <jats:p>We demonstrate that ibudilast-treatment of transgenic rats mitigated hippocampal-dependent spatial memory deficits, as well as hippocampal (hilar subregion) amyloid plaque and tau paired-helical filament load, and microgliosis compared to untreated transgenic rat. Neuronal density analysed across all hippocampal regions was similar in ibudilast-treated transgenic compared to untreated transgenic rats. Interestingly, RNA sequencing analysis of hippocampal tissue showed that ibudilast-treatment affects gene expression levels of the TLR and ubiquitin-proteasome pathways differentially in male and female transgenic rats. Based on the TLR4 signalling pathway, our RNA sequencing data suggest that ibudilast-treatment inhibits IRAK1 activity by increasing expression of its negative regulator IRAK3, and\/or by altering TRAF6 and other TLR-related ubiquitin ligase and conjugase levels.<\/jats:p>\n                  <jats:p>Our results support that ibudilast can serve as a repurposed drug that targets multiple pathways including TLR signalling and the ubiquitin\/proteasome pathway to reduce cognitive deficits and pathology relevant to Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awac136","type":"journal-article","created":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T02:47:43Z","timestamp":1649731663000},"page":"898-911","source":"Crossref","is-referenced-by-count":57,"title":["Repurposing ibudilast to mitigate Alzheimer\u2019s disease by targeting inflammation"],"prefix":"10.1093","volume":"146","author":[{"given":"Giovanni","family":"Oliveros","sequence":"first","affiliation":[{"name":"Program in Biochemistry, The Graduate Center, CUNY , 365 5th Ave, New York, NY 10016 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles H","family":"Wallace","sequence":"additional","affiliation":[{"name":"Program in Biochemistry, The Graduate Center, CUNY , 365 5th Ave, New York, NY 10016 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osama","family":"Chaudry","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Hunter College , 695 Park Ave, New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Hunter College , 695 Park Ave, New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9692-1290","authenticated-orcid":false,"given":"Yue","family":"Qiu","sequence":"additional","affiliation":[{"name":"Program in Biology, The Graduate Center, CUNY , 365 5th Ave, New York, NY 10016 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Hunter College , 695 Park Ave, New York, NY 10065 , USA"},{"name":"Program in Biology, The Graduate Center, CUNY , 365 5th Ave, New York, NY 10016 , USA"},{"name":"Program in Computer Science and Biochemistry, The Graduate Center , 365 5th Ave, New York NY 10016 , USA"},{"name":"Helen and Robert Appel Alzheimer\u2019s disease Research Institute, Feil Family Brain & Mind Research Institute, Weill Cornell Medicine, Cornell University , 411 E 69th St, New York, NY 10021 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Rockwell","sequence":"additional","affiliation":[{"name":"Program in Biochemistry, The Graduate Center, CUNY , 365 5th Ave, New York, NY 10016 , USA"},{"name":"Department of Biological Sciences, Hunter College , 695 Park Ave, New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria E","family":"Figueiredo-Pereira","sequence":"additional","affiliation":[{"name":"Program in Biochemistry, The Graduate Center, CUNY , 365 5th Ave, New York, NY 10016 , USA"},{"name":"Department of Biological Sciences, Hunter College , 695 Park Ave, New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5131-4315","authenticated-orcid":false,"given":"Peter A","family":"Serrano","sequence":"additional","affiliation":[{"name":"Program in Biochemistry, The Graduate Center, CUNY , 365 5th Ave, New York, NY 10016 , 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