RT info:eu-repo/semantics/article
T1 Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy
A1 Tapias, Victor
A1 Jainuddin, Shari
A1 Ahuja, Manuj
A1 Stack, Cliona
A1 Elipenahli, Ceyhan
A1 Vignisse, Julie
A1 Gerges, Meri
A1 Starkova, Natalia
A1 Xu, Hui
A1 Starkov, Anatoly A
A1 Bettendorff, Lucien
A1 Hushpulian, Dmitry M
A1 Smirnova, Natalya A
A1 Gazaryan, Irina G
A1 Kaidery, Navneet A
A1 Wakade, Sushama
A1 Calingasan, Noel Y
A1 Thomas, Bobby
A1 Gibson, Gary E
A1 Dumont, Magali
A1 Beal, M Flint
AB 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.
SN 0964-6906
YR 2018
FD 2018
LK https://uvadoc.uva.es/handle/10324/63891
UL https://uvadoc.uva.es/handle/10324/63891
LA eng
NO Human Molecular Genetics, Agosto 2018, vol. 27, n. 16, p. 2874-2892
NO Producción Científica
DS UVaDOC
RD 02-dic-2024