Targeting the Nrf2/Amyloid-Beta Liaison in Alzheimer's Disease: A Rational Approach

Amyloid is a prominent feature of Alzheimer's disease (AD). Yet, a linear linkage between amyloid-beta peptide (A beta) and the disease onset and progression has recently been questioned. In this context, the crucial partnership between A beta and Nrf2 pathways is acquiring paramount importance, offering prospects for deciphering the A beta-centered disease network. Here, we report on a new class of antiaggregating agents rationally designed to simultaneously activate transcription-based antioxidant responses, whose lead 1 showed interesting properties in a preliminary investigation. Relying on the requirements of A beta recognition, we identified the catechol derivative 12. In SH-SYSY neuroblastoma cells, 12 combined remarkable free radical scavenger properties to the ability to trigger the Nrf2 pathway and induce the Nrf2-dependent defensive gene NQO1 by means of electrophilic activation of the transcriptional response. Moreover, 12 prevented the formation of cytotoxic stable oligomeric intermediates, being significantly more effective, and per se less toxic, than prototype 1. More importantly, as differ chemical features were exploited to regulate Nrf2 and A beta activities, the two pathways could be tuned independently. These findings point to compound 12 and its derivatives as promising tools for investigating the therapeutic potential of the Nrf2/A beta cellular network, laying foundation for generating new drug leads to confront AD.