Nrf2: a dark horse in Alzheimer's disease treatment

Alzheimer's disease (AD), an age-dependent neurodegenerative disorder, is the main cause of dementia. Common hallmarks of AD include the amyloid β-peptide (Aβ) aggregation, high levels of hyperphosphorylated tau protein (p-tau) and failure in redox homeostasis. To date, all proposed drugs affecting Aβ and/or p-tau have been failed in clinical trials. A decline in the expression of the transcription factor Nrf2 (nuclear factor-erythroid 2-p45 derived factor 2) and its driven genes (NQO1, HO-1, and GCLC), and alteration of the Nrf2-related pathways have been observed in AD brains. Nrf2 plays a critical role in maintaining cellular redox homeostasis and regulating inflammation response. Nrf2 activation also provides cytoprotection against increasing pathologies including neurodegenerative diseases. These lines of evidence imply that Nrf2 activation may be a novel AD treatment option. Interestingly, recent studies have also demonstrated that Nrf2 interferes with several key pathogenic processes in AD including Aβ and p-tau pathways. The current review aims to provide insights into the role of Nrf2 in AD. Also, we discuss the progress and challenges regarding the Nrf2 activators for AD treatment.