Dementia Research: What Can Nrf2 Do For You—and Our Aging Brains?

By Tomislav Babic, M.D., Ph.D.,

Dementia, Nrf2, Aging Brain

Nrf2 has garnered a lot of attention in the field of dementia research. Following are some of the latest scientific breakthroughs that may influence the way we approach central nervous system (CNS) and dementia clinical research over the next few years.

The Role of Nrf2 on the Aging Brain

Nrf2 is a transcription factor that controls the expression of about 1% of human genes, including an important antioxidant pathway: Antioxidant Response Element, which helps protect against oxidative damage triggered by injury and inflammation.

It works like this: Under normal conditions, Nrf2 remains in the cytoplasm, where it is quickly degraded, with a half-life of only 20 minutes. But under oxidative stress, Nrf2 travels to the nucleus, binds to a DNA promoter, and initiates the transcription of antioxidative genes and their proteins, promulgating antioxidants throughout the body, including in the brain.

Main Risk Factor for Parkinson’s Disease

 But as we get older, Nrf2 declines in activity—and that’s the main risk factor for Parkinson’s disease and other forms of dementia. That’s why CNS clinical researchers are now examining how manipulating the cells to continue to activate Nrf2 even in the aging brain may be a new avenue for dementia research.

Dementia Research and Dimethyl Fumarate

Recently, researchers put Dimethyl Fumarate (DMF)—an established treatment for Multiple Sclerosis—to the test, launching a preclinical study aimed at determining whether targeting Nrf2 with DMF might address the pathology of Parkinson’s disease, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation.

Targeting Nrf2 in Parkinson’s Patients

Dementia researchers found that DMF protected nigral dopaminergic neurons against α-synucleinopathy, among other protective effects—and in vitro studies indicated that this neuroprotective effect was correlated with altered regulation of certain autophagy markers and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. And in postmortem samples of Parkinson’s disease patients, the cytoprotective proteins associated with Nrf2 expression were partly sequestered in Lewy Bodies. In summary, the study showed substantial support for treating Parkinson’s disease—and targeting Nrf2 in Parkinson’s patients—with DMF.

How We’re Contributing to the Aging Brain Research

During Worldwide’s more than 30 years of neuroscience clinical trials experience, we’ve seen numerous groundbreaking developments, including repurposing treatments from one area of CNS clinical research to another. This is exactly why we’re continuously improving how we approach CNS clinical research. We look forward to seeing how Nrf2, and regulators like DMF, will continue to play a role in therapies for the aging brain!

Tomislav Babic, M.D., Ph.D.,  is Vice President of Medical and Scientific Affairs/Neuroscience at Worldwide Clinical Trials