NRF2 in the Oxidative Stress of Alzheimer's Disease
There are many ways of looking at the pathology of Alzheimer's disease, as it is very complex, layered condition. One of these viewpoints is to note that levels of oxidative stress increase in the Alzheimer's brain, stressing and killing cells. Researchers here report on their investigation of changes in the NRF2-centered regulation of cellular antioxidant systems that take pace in the Alzheimer's brain. A decline in antoxidants accelerates the progression of cell death and dysfunction, but this can be slowed or prevented by suitably targeted intervention aimed at maintaining NRF2 activity. Whether or not this is too far downstream of the causes of Alzheimer's disease to be useful in human patients remains to be seen, but there is enough of a benefit in animal models to ensure continued efforts to build drugs that target this mechanism.
A protein called Nuclear factor erythroid 2-related factor 2 (Nrf2) is regularly activated in response to oxidative stress to protect the brain from oxidative damage. But in the brain of someone with Alzheimer's disease (AD), Nrf2 defense against oxidative stress declines. How that occurs in AD was unknown. A new study found that a protein called Slingshot Homolog-1, or SSH1, stops Nrf2 from carrying out its protective biological activity.
Genetically eliminating SSH1 in mouse models of AD increases Nrf2 activation and slows the development of oxidative damage and buildup of toxic plaques and tangles in the brain - both risk factors for AD. As a result, the regular connections between brain cells are maintained and degeneration of brain nerve cells is avoided.