Title | Repurposing ibudilast to mitigate Alzheimer's disease by targeting inflammation. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Oliveros G, Wallace CH, Chaudry O, Liu Q, Qiu Y, Xie L, Rockwell P, Figueiredo-Pereira ME, Serrano PA |
Journal | Brain |
Volume | 146 |
Issue | 3 |
Pagination | 898-911 |
Date Published | 2023 Mar 01 |
ISSN | 1460-2156 |
Keywords | Alzheimer Disease, Amyloid beta-Peptides, Animals, Disease Models, Animal, Drug Repositioning, Female, Inflammation, Male, Memory Disorders, Mice, Mice, Transgenic, Plaque, Amyloid, Proteasome Endopeptidase Complex, Rats, Rats, Transgenic, Toll-Like Receptor 4, Ubiquitins |
Abstract | Alzheimer's disease is a multifactorial disease that exhibits cognitive deficits, neuronal loss, amyloid plaques, neurofibrillary tangles and neuroinflammation in the brain. 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's disease using patients' tissue samples. Our predictive modelling framework identified ibudilast as a drug with repurposing potential to treat Alzheimer's 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. 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's 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's disease patients. Following long-term treatment with ibudilast, transgenic rats were evaluated at 11 months of age for spatial memory performance and Alzheimer's disease pathology. 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. 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's disease. |
DOI | 10.1093/brain/awac136 |
Alternate Journal | Brain |
PubMed ID | 35411386 |
PubMed Central ID | PMC10226755 |
Grant List | R01 AG057555 / AG / NIA NIH HHS / United States R25 GM060665 / GM / NIGMS NIH HHS / United States |