Modulation of Metal– Amyloid‐ β Reactivity by a Rationally Designed Small Molecule for Elucidating the In Vivo Link of Metal – Amyloid‐ β Complexes to the Pathogenesis of Alzheimer's Disease

The abnormal aggregation of amyloid‐β (Aβ), an intrinsically disordered peptide (IDP), has been implicated in the development of Alzheimer's disease (AD). Recent evidence suggests that other factors including metals and reactive oxygen species (ROS) are involved in the progression of AD. Metal ions can interact with Aβ generating toxic oligomers and ROS in vitro ; however, the involvement of metal–Aβ in AD pathology in vivo remains elusive. To solve this uncertainty, we have developed a chemical tool ( L2‐b ) that specifically targets metal–Aβ over metal‐free Aβ and modulates their reactivity ( i.e. , Aβ aggregation, ROS formation). Upon treatment of L2‐b to 5XFAD AD mice, (i) metal–Aβ species were targeted and modulated in the brain; (ii) Aβ pathology was reduced; and (iii) cognitive deficits were improved. To establish a structure‐reactivity relationship between L2‐b and metal–Aβ L2‐b derivatives were prepared and investigated. Together, our studies present the direct contribution of metal–Aβ complexes to AD pathogenesis as well as provide a foundation of developing small molecules capable of targeting metal–Aβ and regulating metal–Aβ reactivity in vivo .