A rationally designed small molecule for identifying an link between metal-amyloid-β complexes and the pathogenesis of Alzheimer's disease.

Multiple factors, including amyloid-β (Aβ), metals, and reactive oxygen species (ROS), are involved in the development of Alzheimer's disease (AD). Metal ions can interact with Aβ species generating toxic oligomers and ROS ; however, the involvement of metal-Aβ complexes in AD pathology remains unclear. To solve this uncertainty, we have developed a chemical tool () that specifically targets metal-Aβ complexes and modulates their reactivity (, metal-Aβ aggregation, toxic oligomer formation, and ROS production). Through the studies presented herein, we demonstrate that is able to specifically interact with metal-Aβ complexes over metal-free Aβ analogues, redirect metal-Aβ aggregation into off-pathway, nontoxic less structured Aβ aggregates, and diminish metal-Aβ-induced ROS production, overall mitigating metal-Aβ-triggered toxicity, confirmed by multidisciplinary approaches. is also verified to enter the brain with relative metabolic stability. Most importantly, upon treatment of 5XFAD AD mice with , (i) metal-Aβ complexes are targeted and modulated in the brain; (ii) amyloid pathology is reduced; and (iii) cognition deficits are significantly improved. To the best of our knowledge, by employing an chemical tool specifically prepared for investigating metal-Aβ complexes, we report for the first time experimental evidence that metal-Aβ complexes are related directly to AD pathogenesis.