Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice

Peroxisome proliferator-activated receptors (PPARs) are ligand-mediated transcription factors, which control both lipid and energy metabolism and inflammation pathways. PPAR agonists are effective in the treatment of metabolic diseases and, more recently, neurodegenerative diseases, in which they show promising neuroprotective effects. We studied the effects of the pan-PPAR agonist bezafibrate on tau pathology, inflammation, lipid metabolism and behavior in transgenic mice with the P301S human tau mutation, which causes familial frontotemporal lobar degeneration. Bezafibrate treatment significantly decreased tau hyperphosphorylation using AT8 staining and the number of MC1-positive neurons. Bezafibrate treatment also diminished microglial activation and expression of both inducible nitric oxide synthase and cyclooxygenase 2. Additionally, the drug differentially affected the brain and brown fat lipidome of control and P301S mice, preventing lipid vacuoles in brown fat. These effects were associated with behavioral improvement, as evidenced by reduced hyperactivity and disinhibition in the P301S mice. Bezafibrate therefore exerts neuroprotective effects in a mouse model of tauopathy, as shown by decreased tau pathology and behavioral improvement. Since bezafibrate was given to the mice before tau pathology had developed, our data suggest that bezafibrate exerts a preventive effect on both tau pathology and its behavioral consequences. Bezafibrate is therefore a promising agent for the treatment of neurodegenerative diseases associated with tau pathology

Benfotiamine Treatment Activates the Nrf2/ARE Pathway and is Neuroprotective in a Transgenic Mouse Model of Tauopathy

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

Benfotiamine Treatment Activates Nrf2/ARE Pathway and is Neuroprotective in a Transgenic Mouse Model of Tauopathy

peer reviewedImpaired glucose metabolism, decreased levels of thiamine (vitamin B1) and its phosphate esters, and downregulated activity of thiamine-dependent enzymes, such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase have been linked to Alzheimer’s disease (AD). Thiamine-deficient mice exhibit increased amyloid deposition, tau hyperphosphorylation, and oxidative damage1. Experimental evidence has shown that benfotiamine (BFT), a synthetic S-acyl derivative of thiamine, rescued cognitive deficits and reduced amyloid burden in APP/PS1 mice2. We investigated whether BFT confers neuroprotection against tau phosphorylation and the generation of neurofibrillary tangles (NFTs) ‒ which causes frontotemporal dementia in humans ‒ in a mouse model of tauopathy. Exposure to BFT resulted in increased lifespan, behavioral improvement, reduced and glycated tau and NFTs, and prevented neuronal death in P301S transgenic (TG) mice. In addition, BFT administration significantly ameliorated mitochondrial dysfunction, attenuated oxidative damage, and decreased the expression of several pro-inflammatory mediators, consistent with a possible activation of the Nrf2/ARE neuroprotective pathway. Accordingly, we found that BFT (but not thiamine) triggers the expression of Nrf2/ARE-dependent genes in wild-type (WT) but not in Nrf2-deficient fibroblasts. Our findings suggest that BFT is a promising therapeutic agent for the treatment of tauopathies