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

Abstract

Multiple factors, including amyloid-beta (A beta), metals, and reactive oxygen species (ROS), are involved in the development of Alzheimer's disease (AD). Metal ions can interact with A beta species generating toxic oligomers and ROS in vitro; however, the involvement of metal-A beta complexes in AD pathology in vivo remains unclear. To solve this uncertainty, we have developed a chemical tool (L2-b) that specifically targets metal-A beta complexes and modulates their reactivity (i.e., metal-A beta aggregation, toxic oligomer formation, and ROS production). Through the studies presented herein, we demonstrate that L2-b is able to specifically interact with metal-A beta complexes over metal-free A beta analogues, redirect metal-A beta aggregation into off-pathway, nontoxic less structured A beta aggregates, and diminish metal-A beta-induced ROS production, overall mitigating metal-A beta-triggered toxicity, confirmed by multidisciplinary approaches. L2-b is also verified to enter the brain in vivo with relative metabolic stability. Most importantly, upon treatment of 5XFAD AD mice with L2-b, (i) metal-A beta 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 in vivo chemical tool specifically prepared for investigating metal-A beta complexes, we report for the first time experimental evidence that metal-A beta complexes are related directly to AD pathogenesis.