Keap1 and GSK-3 in the regulation of Nrf2 in Alzheimer’s disease.
(A) Aβ42 peptide inhibits activity of Nrf2, and this may explain the increased presence of xenobiotic and oxidative stress markers observed in Alzheimer’s disease. (B) Although lithium can activate Nrf2 at high concentrations, its protective effect against Aβ42 toxicity appears to be mainly Nrf2-independent, reducing Aβ42 levels by inhibiting translation and preventing oxidative damage. More specific GSK-3 inhibitors are required to confirm the precise role of GSK-3 in rescuing Nrf2 deficits in neurodegenerative disease. (C) Genetic and pharmacological inhibition of Keap1 can rescue Aβ42-induced Nrf2 inhibition and neuronal toxicity by preventing xenobiotic damage and activating degradation of Aβ42 peptide. (D) Keap1 inhibitors may serve as effective therapies for AD and, in combination with GSK-3 inhibitors, may provide added benefits in preventing neurodegeneration through non-overlapping mechanisms.