Modifying Keap1-Nrf2 Signalling to Maintain Neuronal Integrity in Alzheimer's Disease

  • Kerr, Fiona (PI)
  • Wells, Geoffrey (CoI)
  • Wray, Selina (CoI)

Project Details

Description

Alzheimer’s disease (AD) is the leading cause of dementia in humans, affecting almost 47 million patients world-wide. Current therapies do not slow-down the progression of memory loss in AD and this presents a significant healthcare challenge for future generations. A priority area for research is therefore to discover new drugs to halt dementia by finding ways to protect nerve cells as disease progresses.
Most scientists believe that, early in the pathological process of AD, deposits of a protein called amyloid (Aβ) build up and cause damage to nerve cell connections (synapses), which are important for transmitting messages in the brain. Since the protein Nrf2 is a master controller of cell protection, the idea behind my research is that it may prevent synapse damage in AD even after the build-up of amyloid has begun. Current Nrf2 enhancing drugs protect against memory loss in mouse models of AD, but display toxic side-effects in humans. My published studies, using fruit flies and mouse nerve cells, suggest that blocking another protein, Keap1 (which dampens Nrf2), is a novel and safe way to maintain Nrf2 and prevent amyloid damage. Research is now required to understand the relevance of these findings to human AD and when and why Keap1-Nrf2 disruption has beneficial effects as disease progresses.
This project will address these questions using pioneering human induced pluripotent stem cell (hiPSC) technologies to generate nerve cells from human AD and control patients in a dish. Aβ released into the growth media of AD-patient cells will be used to treat healthy human nerve cells and the damage to synapses will be tracked. A new class of chemical Keap-Nrf2 blockers will then be used to explore when (before or after Aβ) and why blocking Keap1 can protect nerve cells in human AD. Synapse loss will be determined by counting the number of connections between nerve cells using advanced confocal microscopy. Molecular biology techniques will be used to uncover new molecules which may mediate the effect of Keap1-Nrf2 blockers in protecting nerve cells from Aβ damage.
This project has clear translational potential, by understanding the relevance of Keap1-Nrf2 disruption to human AD, determining the disease stages at which this strategy has beneficial effect and finding clues to the molecules mediating its protection of nerve cells. This will provide a basis for further investigation to establish the potential of these molecules as targets for disease-altering drugs, using human neurons and animal models of AD. As Nrf2 is a generalised mediator of neuronal protection the outcomes of this study have the added benefit of treating AD as well as other forms of dementia, and therefore has the potential to lead to life-changing treatments for the benefit of millions of patients world-wide.
StatusFinished
Effective start/end date1/07/1831/12/19

Funding

  • Tenovus Scotland: £19,879.00

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