Michael W. Beck,ab Shin Bi Oh,c Richard A. Kerr,b Hyuck Jin Lee,ab So Hee Kim,c Sujeong Kim,c Milim Jang,a Brandon T. Ruotolo,*b Joo-Yong Lee*cd and Mi Hee Lim*ae
a Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Republic of Korea
b Department of Chemistry, University of Michigan, Ann Arbor, USA
c Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea
d Department of Neurology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
e Life Sciences Institute, University of Michigan, Ann Arbor, USA
* Corresponding authors
Abstract
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 in vitro; however, the involvement of metal-Aβ complexes in AD pathology in vivo remains unclear. To solve this uncertainty, we have developed a chemical tool (L2-b) that specifically targets metal-Aβ complexes and modulates their reactivity (i.e., metal-Aβ aggregation, toxic oligomer formation, and ROS production). Through the studies presented herein, we demonstrate that L2-b 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. 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-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 in vivo 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.