Article (Scientific journals)
Benfotiamine Treatment Activates the Nrf2/ARE Pathway and is Neuroprotective in a Transgenic Mouse Model of Tauopathy
Tapias, Victor; Jainuddin, Shari; Ahuja, Manuj et al.
2018In Human Molecular Genetics, 27 (16), p. 2874-2892
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Keywords :
Thiamine; Benfotiamine; Neurodegenerative diseases; Tauopathy; Oxidative stress; Inflammation
Abstract :
[en] 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 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/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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Tapias, Victor
Jainuddin, Shari
Ahuja, Manuj
Stack, Cliona
Elipenahli, Ceyhan
Vignisse, Julie;  Université de Liège > Département des maladies infectieuses et parasitaires (DMI) > Mycologie vétérinaire
Gerges, Meri
Starkova, Natalia
Xu, Hui
Starkov, Anatoly A.
Bettendorff, Lucien  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie humaine et pathologique
Hushpulian, Dmitry M.
Smirnova, Natalya A.
Gazaryan, Irina G.
Kaidery, Navneet A.
Wakade, Sushama
Calingasan, Noel Y.
Thomas, Bobby
Gibson, Gary E.
Dumont, Magali
Beal, M. Flint
More authors (11 more) Less
Language :
English
Title :
Benfotiamine Treatment Activates the Nrf2/ARE Pathway and is Neuroprotective in a Transgenic Mouse Model of Tauopathy
Publication date :
2018
Journal title :
Human Molecular Genetics
ISSN :
0964-6906
eISSN :
1460-2083
Publisher :
Oxford University Press, United Kingdom
Volume :
27
Issue :
16
Pages :
2874-2892
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
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