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Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy
- Source :
- Human Molecular Genetics. 27:2874-2892
- Publication Year :
- 2018
- Publisher :
- Oxford University Press (OUP), 2018.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....507664ee62694dda9acf5b8e277c32c5