Discovery of Chemicals to Either Clear or Indicate Amyloid Aggregates by Targeting Memory‐Impairing Anti‐Parallel Aβ Dimers

• DOI: 10.1002/ange.202002574
• Publication Date: 2020-03-31T20:02:58Z
• Authors: Jinny Claire Lee; Hye Yun Kim; Sejin Lee; Jisu Shin; Hyunjin Vincent Kim; Kyeonghwan Kim; Seungyeop Baek; Donghee Lee; Hanna Jeon; DaWon Kim; Seung‐Hoon Yang; Gyoonhee Han; Keunwan Park; Jaeho Choi; Jinwoo Park; Jason A. Moss; Kim D. Janda; YoungSoo Kim
• Keywords: Male; 0301 basic medicine; Amyloid; Mice, Inbred ICR; Amyloid beta-Peptides; Mice, Transgenic; Plaque, Amyloid; 3. Good health; Mice; 03 medical and health sciences; Alzheimer Disease; Memory; Drug Discovery; Animals; Female; Maze Learning; Dimerization

AbstractAmyloid‐β (Aβ) oligomers are implicated in Alzheimer disease (AD). However, their unstable nature and heterogeneous state disrupts elucidation of their explicit role in AD progression, impeding the development of tools targeting soluble Aβ oligomers. Herein parallel and anti‐parallel variants of Aβ(1–40) dimers were designed and synthesized, and their pathogenic properties in AD models characterized. Anti‐parallel dimers induced cognitive impairments with increased amyloidogenesis and cytotoxicity, and this dimer was then used in a screening platform. Through screening, two FDA‐approved drugs, Oxytetracycline and Sunitinib, were identified to dissociate Aβ oligomers and plaques to monomers in 5XFAD transgenic mice. In addition, fluorescent Astrophloxine was shown to detect aggregated Aβ in brain tissue and cerebrospinal fluid samples of AD mice. This screening platform provides a stable and homogeneous environment for observing Aβ interactions with dimer‐specific molecules.