Self-triggered click reaction in an Alzheimer's disease model: in situ bifunctional drug synthesis catalyzed by neurotoxic copper accumulated in amyloid-β plaques

Abstract

Cu is one of the essential elements for life. Its dyshomeostasis has been demonstrated to be closely related to neurodegenerative disorders, such as Alzheimer's disease (AD), which is characterized by amyloid-β (Aβ) aggregation and Cu accumulation. It is a great challenge as to how to take advantage of neurotoxic Cu to fight disease and make it helpful. Herein, we report that the accumulated Cu in Aβ plaques can effectively catalyze an azide–alkyne bioorthogonal cycloaddition reaction for fluorophore activation and drug synthesis in living cells, a transgenic AD model of Caenorhabditis elegans CL2006, and brain slices of triple transgenic AD mice. More importantly, the in situ synthesized bifunctional drug 6 can disassemble Aβ–Cu aggregates by extracting Cu and photo-oxygenating Aβ synergistically, suppressing Aβ-mediated paralysis and diminishing the locomotion defects of the AD model CL2006 strain. Our results demonstrate that taking the accumulated Cu ions in the Aβ plaque for an in situ click reaction can achieve both a self-triggered and self-regulated drug synthesis for AD therapy. To the best of our knowledge, a click reaction catalyzed by local Cu in a physiological environment has not been reported. This work may open up a new avenue for in situ multifunctional drug synthesis by using endogenous neurotoxic metal ions for the treatment of neurodegenerative diseases.