Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy
| Autor: | Julie Vignisse, Bobby Thomas, Natalia N. Starkova, Lucien Bettendorff, Meri Gerges, Flint Beal, Manuj Ahuja, Cliona Stack, Ceyhan Elipenahli, Irina G. Gazaryan, N. A. Smirnova, Magali Dumont, Anatoly A. Starkov, Gary E. Gibson, Shari Jainuddin, Victor Tapias, Sushama Wakade, Navneet Ammal Kaidery, Hui Xu, D. M. Hushpulian, Noel Y. Calingasan |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Genetically modified mouse NF-E2-Related Factor 2 Amyloid beta Mice Transgenic tau Proteins Pharmacology Biology Protein Aggregation Pathological Neuroprotection Progressive supranuclear palsy Mice 03 medical and health sciences 0302 clinical medicine Genetics medicine Amyloid precursor protein Animals Humans Thiamine Molecular Biology Genetics (clinical) Amyloid beta-Peptides Kelch-Like ECH-Associated Protein 1 Brain General Medicine medicine.disease Antioxidant Response Elements Disease Models Animal Oxidative Stress 030104 developmental biology Benfotiamine Tauopathies biology.protein Original Article Tauopathy 030217 neurology & neurosurgery Signal Transduction medicine.drug |
| Zdroj: | Human Molecular Genetics. 27:2874-2892 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddy201 |
| Popis: | Impaired glucose metabolism, decreased levels of thiamine and its phosphate esters, and reduced activity of thiamine-dependent enzymes, such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and transketolase occur in Alzheimer’s disease (AD). Thiamine deficiency exacerbates amyloid beta (Aβ) deposition, tau hyperphosphorylation and oxidative stress. Benfotiamine (BFT) rescued cognitive deficits and reduced Aβ burden in amyloid precursor protein (APP)/PS1 mice. In this study, we examined whether BFT confers neuroprotection against tau phosphorylation and the generation of neurofibrillary tangles (NFTs) in the P301S mouse model of tauopathy. Chronic dietary treatment with BFT increased lifespan, improved behavior, reduced glycated tau, decreased NFTs and prevented death of motor neurons. BFT administration significantly ameliorated mitochondrial dysfunction and attenuated oxidative damage and inflammation. We found that BFT and its metabolites (but not thiamine) trigger the expression of Nrf2/antioxidant response element (ARE)-dependent genes in mouse brain as well as in wild-type but not Nrf2-deficient fibroblasts. Active metabolites were more potent in activating the Nrf2 target genes than the parent molecule BFT. Docking studies showed that BFT and its metabolites (but not thiamine) bind to Keap1 with high affinity. These findings demonstrate that BFT activates the Nrf2/ARE pathway and is a promising therapeutic agent for the treatment of diseases with tau pathology, such as AD, frontotemporal dementia and progressive supranuclear palsy. |
| Databáze: | OpenAIRE |
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