Therapeutic Potential and Anti-Amyloidosis Mechanisms of Tert-Butylhydroquinone for Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain, one of the pathological features of AD, is considered to be a central disease-causing and disease-promoting event in AD. In this study, we showed that feeding male AβPP/PS1 transgenic mice, a well established mouse model of AD, with a diet containing phenolic antioxidant tert-butylhydroquinone (TBHQ) dramatically reduced brain Aβ load with no significant effect on the amounts of alpha- and beta-C-terminal fragments or full-length AβPP. Further studies showed that TBHQ diet inhibited the expression of plasminogen activator inhibitor-1 (PAI-1), a protease inhibitor which plays a critical role in brain Aβ accumulation in AD, accompanied by increases in the activities of tissue type and urokinase type plasminogen activators (tPA and uPA) as well as plasmin. Moreover, we showed that TBHQ diet increased the expression of low density lipoprotein related protein-1, a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, and plasma Aβ40 and Aβ42 levels. We also showed that TBHQ diet increased the concentration of glutathione, an important antioxidant, and suppressed the expression of NADPH oxidase 2 as well as lipid peroxidation. Collectively, our data suggest that TBHQ may have therapeutic potential for AD by increasing brain antioxidant capacity/reducing oxidative stress level and by stimulating Aβ degradation/clearance pathways.

Transforming growth factor β suppresses glutamate–cysteine ligase gene expression and induces oxidative stress in a lung fibrosis model

“…Concentrations of urea in BALF and in the plasma were measured using a commercially available kit (Teco Diagnostics, Anaheim, CA) and the dilution factors of epithelial lining fluid (ELF) were calculated based on urea concentrations in the plasma and in BALF, which were used to normalize the antioxidant concentrations in ELF. Total GSH contents in lung tissue were measured using a recycling assay as we have described previously [42]. The protein contents were measured by a BCA kit and GSH concentrations calculated based on standard curve run together with the samples and normalized by protein content.…”

NADPH Oxidase and Neurodegeneration

“…Gp91ds-tat, a Nox2 inhibitory peptide, decreased both oxidative stress and AD pathology in aged mice [59]. Also, It has been recently shown that feeding AβPP/PS1 double transgenic mice, a mouse model of AD, with a diet containing phenolic antioxidant tert-butylhydroquinone, inhibits Nox2 protein expression and suppressed lipid peroxidation in the cerebral cortex and hippocampus [60]. It was also found that age-dependent increases of Aβ had a significant linear relationship with both Nox4 activity and cognitive performance in “humanized” APP×PS1 knock-in mice [61].…”

Sequential Upregulation of Superoxide Dismutase 2 and Heme Oxygenase 1 by tert-Butylhydroquinone Protects Mitochondria during Oxidative Stress

“…Previous studies have shown that tBHQ exerts protective effects in multiple neurodegenerative conditions, including stroke (Shih et al, 2005), traumatic brain injury (Jin et al, 2011;Lu et al, 2014), Parkinson's disease (Hara et al, 2003), and Alzheimer's disease (Eftekharzadeh et al, 2010;Akhter et al, 2011). However, the underlying mechanisms of tBHQ's protective role have not been elucidated.…”