Attenuation of Nrf2/Keap1/ARE in Alzheimer's Disease by Plant Secondary Metabolites: A Mechanistic Review

Alzheimer’s disease (AD) is a progressive neuronal/cognitional dysfunction, leading to disability and death. Despite advances in revealing the pathophysiological mechanisms behind AD, no effective treatment has yet been provided. It urges the need for finding novel multi-target agents in combating the complex dysregulated mechanisms in AD. Amongst the dysregulated pathophysiological pathways in AD, oxidative stress seems to play a critical role in the pathogenesis progression of AD, with a dominant role of nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1)/antioxidant responsive elements (ARE) pathway. In the present study, a comprehensive review was conducted using the existing electronic databases, including PubMed, Medline, Web of Science, and Scopus, as well as related articles in the field. Nrf2/Keap1/ARE has shown to be the upstream orchestrate of oxidative pathways, which also ameliorates various inflammatory and apoptotic pathways. So, developing multi-target agents with higher efficacy and lower side effects could pave the road in the prevention/management of AD. The plant kingdom is now a great source of natural secondary metabolites in targeting Nrf2/Keap1/ARE. Among natural entities, phenolic compounds, alkaloids, terpene/terpenoids, carotenoids, sulfur-compounds, as well as some other miscellaneous plant-derived compounds have shown promising future accordingly. Prevailing evidence has shown that activating Nrf2/ARE and downstream antioxidant enzymes, as well as inhibiting Keap1 could play hopeful roles in overcoming AD. The current review highlights the neuroprotective effects of plant secondary metabolites through targeting Nrf2/Keap1/ARE and downstream interconnected mediators in combating AD.