Aβ Oligomer Toxicity-Reducing Therapy for the Prevention of Alzheimer's Disease: Importance of the Nrf2 and PPARγ Pathways

Recent studies have revealed that soluble amyloid-beta oligomers (A beta Os) play a pathogenetic role in Alzheimer's disease (AD). Indeed, A beta Os induce neurotoxic and synaptotoxic effects and are also critically involved in neuroinflammation. Oxidative stress appears to be a crucial event underlying these pathological effects of A beta Os. From a therapeutic standpoint, new drugs for AD designed to remove A beta Os or inhibit the formation of A beta Os are currently being developed. However, it is also worth considering strategies for preventing A beta O toxicity itself. In particular, small molecules with A beta O toxicity-reducing activity have potential as drug candidates. Among such small molecules, those that can enhance Nrf2 and/or PPAR gamma activity can effectively inhibit A beta O toxicity. In this review, I summarize studies on the small molecules that counteract A beta O toxicity and are capable of activating Nrf2 and/or PPAR gamma. I also discuss how these interrelated pathways are involved in the mechanisms by which these small molecules prevent A beta iO-induced neurotoxicity and neuroinflammation. I propose that A beta O toxicity-reducing therapy, designated ATR-T, could be a beneficial, complementary strategy for the prevention and treatment of AD.