Targeting the multifaceted neurotoxicity of Alzheimer's disease by tailored functionalisation of the curcumin scaffold
Ersilia De Lorenzi, Francesca Seghetti, Andrea Tarozzi, Letizia Pruccoli, Cecilia Contardi, Massimo Serra, Alessandra Bisi, Silvia Gobbi, Giulio Vistoli, Silvia Gervasoni, Carla Argentini, G Ghirardo, Giulia Guarato, Genny Orso, Federica Belluti, Rita Maria Concetta Di Martino, Morena Zusso
Abstract
Simultaneous modulation of multifaceted toxicity arising from neuroinflammation, oxidative stress, and mitochondrial dysfunction represents a valuable therapeutic strategy to tackle Alzheimer's disease. Among the significant hallmarks of the disorder, Aβ protein and its aggregation products are well-recognised triggers of the neurotoxic cascade. In this study, by tailored modification of the curcumin-based lead compound 1, we aimed at developing a small library of hybrid compounds targeting Aβ protein oligomerisation and the consequent neurotoxic events. Interestingly, from in vitro studies, analogues 3 and 4, bearing a substituted triazole moiety, emerged as multifunctional agents able to counteract Aβ aggregation, neuroinflammation and oxidative stress. In vivo proof-of-concept evaluations, performed in a Drosophila oxidative stress model, allowed us to identify compound 4 as a promising lead candidate.