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Discovery of Chemicals to Either Clear or Indicate Amyloid Aggregates by Targeting Memory‐Impairing Anti‐Parallel Aβ Dimers
Author(s) -
Lee Jinny Claire,
Kim Hye Yun,
Lee Sejin,
Shin Jisu,
Kim Hyunjin Vincent,
Kim Kyeonghwan,
Baek Seungyeop,
Lee Donghee,
Jeon Hanna,
Kim DaWon,
Yang SeungHoon,
Han Gyoonhee,
Park Keunwan,
Choi Jaeho,
Park Jinwoo,
Moss Jason A.,
Janda Kim D.,
Kim YoungSoo
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202002574
Subject(s) - chemistry , dimer , cytotoxicity , amyloid (mycology) , monomer , genetically modified mouse , homogeneous , oligomer , biophysics , transgene , biochemistry , in vitro , biology , inorganic chemistry , thermodynamics , physics , organic chemistry , gene , polymer
Amyloid‐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.