Nrf2 Gene Could Have Protective Role in Neurons

Increasing the expression of one gene in cells that assist the brain’s neurons protects neurons in mouse models of Alzheimer’s disease. These findings come from a new study published in Nature Communications. The work was led by University of Wisconsin–Madison School of Pharmacy scientists.

The team discovered that increasing the levels of Nrf2 in astrocytes helped neurons greatly reduce the accumulation of tau and beta-amyloid proteins. Mice overexpressing Nrf2 performed better on memory and physical tests. Boosting Nrf2 also reversed the genetic signatures of Alzheimer’s in the mouse models, suggesting that it had a widespread normalizing effect beyond just addressing the clumps of tau and beta-amyloid.

“The extent of the reduction in beta-amyloid and tau and the nearly complete reversal of the genetic changes is very significant,” says lead researcher Jeffrey Johnson, who helped identify Nrf2’s protective role via astrocytes in other neurodegenerative diseases prior to this study. “Over 2,300 genes change in one part of the brain in the Alzheimer’s model. And almost all 2,300 go back to normal. I was stunned. I never thought we’d get that outcome.” To study how the persistent activation of Nrf2 in astrocytes could protect the brain, Johnson’s lab bred mice that both over-accumulated beta-amyloid around neurons, to simulate Alzheimer’s disease, and expressed a lot of Nrf2 in astrocytes. Compared to mice without the boost to Nrf2, those with a lot of the gene had almost 90% less beta-amyloid in their brains. They also had far fewer beta-amyloid plaques.

One symptom of Alzheimer’s, both in mice and humans, is memory loss. Alzheimer’s model mice overexpressing Nrf2 also performed much better in a classic memory test than those without the boosted gene—nearly as well as non-Alzheimer’s mice. And, mice with extra Nrf2 were much better at navigating a tight-rope-like bar, a measure of their balance and coordination.

“Nrf2 overexpression had a very similar impact in both the tau and beta-amyloid models,” says collaborator Giles Hardingham. “In both cases, it’s very clear that Nrf2 in the astrocytes is modulating the neuropathology.”