Reference : Benfotiamine Treatment Activates the Nrf2/ARE Pathway and is Neuroprotective in a Tra...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/224271
Benfotiamine Treatment Activates the Nrf2/ARE Pathway and is Neuroprotective in a Transgenic Mouse Model of Tauopathy
English
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 mailto [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 [> >]
2018
Human Molecular Genetics
Oxford University Press
27
16
2874-2892
Yes (verified by ORBi)
National
0964-6906
1460-2083
United Kingdom
[en] Thiamine ; Benfotiamine ; Neurodegenerative diseases ; Tauopathy ; Oxidative stress ; Inflammation
[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.
Fonds de la Recherche Scientifique (Communauté française de Belgique) - F.R.S.-FNRS
Researchers ; Professionals ; Students
http://hdl.handle.net/2268/224271
10.1093/hmg/ddy201

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