This study is designed to screen potent activators of nuclear factor-erythroid 2 related factor 2 (Nrf2) translation for the treatment or prevention of Alzheimer's disease (AD). Nrf2 regulates the expression of most genes involved with the intrinsic antioxidant response and it has been widely reported with in vivo studies, that activatio of this transcription factor has the potential to ameliorate the progression of Alzheimer's disease. Most known activators of Nrf2 act indirectly by preventing its cytoplasmic degradation mediated by Kelch like ECH-associated protein 1 (Keap1). We recently found a novel regulatory mechanism of Nrf2 at the level of protein translation, and were able to create a biosensor to detect activators of Nrf2 translation. We propose testing this sensor to detect Nrf2 translational activators in 5040 natural-derived compounds library. After screening a library using this assay, those compounds found to activate Nrf2 translation will be examined in secondary screen for anti-AD activity.
Our aim i s to identify novel compounds that activate Nrf2 in cells lines involved with AD.
Studies in mice indicate, that increasing the activity in the brain of the master regulator of the endogenous antioxidant response, Nuclear Factor-erythroid 2 Related Factor 2 (Nrf2) has the potential to ameliorate the progression of Alzheimer's disease (AD), where oxidative stress plays a major role. We found that the expression of Nrf2 is regulated at the translation level by a novel mechanism. In this project, we propose to implement a screening campaign in order to develop novel inducers of Nrf2 translation with the best pharmacological properties for reducing oxidative stress in AD.
| Perez-Leal, Oscar; Barrero, Carlos Alberto; Merali, Salim (2017) Pharmacological stimulation of nuclear factor (erythroid-derived 2)-like 2 translation activates antioxidant responses. J Biol Chem 292:14108-14121 |
