Effective Amelioration of Alzheimer's Disease in Preclinical Models With Electrophilic Compounds via Nrf2 Pathway Activation

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes, with no effective treatments currently available. Oxidative stress has been shown to be associated with AD, but the causal relationship of AD by oxidative stress remains unestablished. Activation of the Nrf2 pathway is a powerful way to counteract oxidative stress. There are lines of evidence that the pathological features, including Aβ deposition, Tau phosphorylation, neuroinflammation, and mitochondrial dysfunction, could be ameliorated by different antioxidant measures. A group of Nrf2 pathway activators, functioning as Michael acceptors, can covalently modify the Keap1 protein. Such a reaction triggers a conformational change of Keap1, facilitating the release of functional Nrf2 and its subsequent translocation into the nucleus. As a result, a cascade of antioxidant related proteins is expressed. Many plant-derived compounds with Nrf2 pathway activation properties were shown to improve the AD symptom in animal models. This review summarizes the phytochemicals and FDA-approved drugs with diverse structure, including isothiocyanates, polyphenols, phenylpropanoids, flavonoids, terpenes, and alkaloids, but all with Nrf2 pathway activation function and effects on the ameliorating effects on AD symptoms. Three of FDA-approved drugs, being Nrf2 activators, are for the disorders in nervous system. Therefore, Nrf2 could be a promising target for future drug development based on rational design or on the screening from the phytochemicals.