Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal and synaptic loss, the accumulation of extracellular deposits of amyloid-beta (Aβ) and the formation of intracellular neurofibrillary tangles. Evidence suggests that the presence of Ab is toxic, and the mechanism of cytotoxicity involves the production of reactive oxidative stress. Given the important role of oxidative stress in AD, therapeutic strategies directed at reducing oxidative damage represent a promising target for neuroprotection. Nrf2 is a transcription factor that regulates the gene expression of a wide variety of cytoprotective phase II detoxification enzymes and antioxidant enzymes through an enhancer sequence known as the antioxidant-responsive element (ARE), and it plays a pivotal role in the ARE-driven cellular defense system against oxidative stress. We found that the expression of Nrf2 is regulated at the translational level by a novel mechanism that requires specific sequences inside the open reading frame. Based on this knowledge, we were able to successfully develop and validate a biosensor to detect small molecules that directly enhance Nrf2 translation. The use of this sensor to screen a natural-derived compound library resulted in the detection of 45 Nrf2 translational enhancers. The challenge now is to execute a hit-to-lead campaign to generate inducers of Nrf2 translation with the best CNS pharmacological properties for reducing oxidative stress in AD.
Moulder Center for Drug Discovery Research
Temple University School of Pharmacy
3307 N Broad Street
Philadelphia, PA 19140