Delineating pathways downstream of Keap1-Nrf2 as targets for neuronal protection in AD. (360G-Wellcome-211451_Z_18_Z)

Nrf2 activators show promise in preventing memory-loss in animal models of AD, but have side-effects in humans. A new class of drugs which activate Nrf2 by blocking its interaction with Keap1, reduce brain damage in Drosophila and mouse neuron AD models. Nrf2 leads to the transcription of hundreds of cytoprotective genes, and we need to understand which of these mediate neuronal protection by Keap1-Nrf2 disruptors and the effectiveness of these compounds in human cells. Using a hiPSC model of AD-associated amyloid toxicity, this project aims to study the effects of a Keap1-Nrf2 disruptor, 18e, on Nrf2 target gene expression in human AD.Changes in Nrf2-pathway gene expression levels following Abeta treatment will be assessed using PCR array profiling. qPCR will then be used to validate these changes and measure the effects of 18e on their expression. A disease-altering treatment for dementia is necessary to improve the lives of the escalating numbers of patients and carers worldwide. This research will provide a first step in identifying the Nrf2-target genes most closely associated with prevention of amyloid damage to human neurons. Targeting Nrf2 genes more selectively may prove useful in the development of safer treatments to protect neurons in AD and other dementias.