Biochemical Society Summer Vacation Scholarship

Project Description

Nrf2, a transcriptional activator of cell protection genes, is an emerging target for neurodegenerative conditions including Alzheimer’s disease (AD). Nrf2 activity is reduced in dementia patients and Nrf2 inducing compounds prevent neuronal damage in animal models. Current Nrf2 activators, however, have exerted toxicity in clinical trials. Direct disruption of the protein-protein interaction (PPI) between Nrf2 and its inhibitor Keap1 is a developing area of drug discovery.
We have shown that Keap1-Nrf2 disrupting compounds can protect against Aβ oligomerinduced toxicity in mouse cortical neurons. Other studies suggest that this pharmacological strategy can exert neuronal protection in vivo using rat models of global cerebral ischaemia. Hence Keap1-Nrf2 inhibitors may maintain Nrf2 signalling in neurodegenerative diseases, whilst limiting the side-effects associated with Nrf2 over-activation.
Further work is required to translate these findings to human neurons, to determine their potential as treatments for AD and other forms of dementia. This project aims to develop human iPSC neuron models of amyloid and hypoxia-induced toxicity, and use these to compare the protective effects of Keap1-Nrf2 disruptors against neuronal damage in AD and vascular dementia. As these are the leading causes of cognitive decline, this study has potential to determine a novel therapeutic avenue for dementia treatment.