Alzheimer's disease (AD) is a neurodegenerative disorder that affects ever growing older population. At present, there are no means to prevent or reverse AD. The defining clinical components of the AD are the neuronal and synaptic loss, the accumulation of extracellular deposits of amyloid-beta (A?) and the formation of intracellular neurofibrillary tangles. Evidence suggests that the presence of A? is toxic, and the mechanism of cytotoxicity involves the production of reactive oxidative stress. A master regulator of antioxidant response is nuclear factor-erythroid 2 related factor 2 (Nrf2), which is deranged in AD. Nrf2 regulates the expression of most genes involved with the intrinsic antioxidant response, and it has been widely reported that activation 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 unique regulatory mechanism of Nrf2 at the level of protein translation and were able to create a biosensor to detect activators of Nrf2 translation. We performed a secondary screen and were able to triage the Nrf2 translational activators to 9 molecules. Our goal now is to identify lead candidates with physiochemical properties that meet the criteria for advancement to in vivo PK and efficacy studies. To accomplish this, we have proposed to use a medicinal chemistry approach to generate novel non-toxic activators of Nrf2 translation.
Alzheimer's disease is an irreversible, progressive brain disease that impairs cognitive functions. This project is aimed at identifying drugs that reduce oxidative stress, which is known to increase toxicity and chronic inflammation in brain cells and contributes to neuron and synaptic deterioration in Alzheimer's disease.