2. Academic Validation
  3. Discovery of Chemicals to Either Clear or Indicate Amyloid Aggregates by Targeting Memory-Impairing Anti-Parallel Aβ Dimers

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

  • Angew Chem Int Ed Engl. 2020 Jul 6;59(28):11491-11500. doi: 10.1002/anie.202002574.
Jinny Claire Lee 1 2,  Hye Yun Kim 1,  Sejin Lee 1 3,  Jisu Shin 1,  Hyunjin Vincent Kim 3,  Kyeonghwan Kim 1,  Seungyeop Baek 1 4,  Donghee Lee 1,  Hanna Jeon 1,  DaWon Kim 1,  Seung-Hoon Yang 5,  Gyoonhee Han 1 4,  Keunwan Park 6,  Jaeho Choi 7,  Jinwoo Park 7,  Jason A Moss 2,  Kim D Janda 2,  YoungSoo Kim 1
Affiliations

Affiliations

  • 1 Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, South Korea.
  • 2 Department of Chemistry, Department of Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, The Worm Institute for Research and Medicine (WIRM), The Scripps Research Institute, La Jolla, CA, 92037, USA.
  • 3 KIST School, University of Science and Technology (UST), Korea Institute of Science and Technology (KIST), Seoul, 02792, South Korea.
  • 4 Department of Biotechnology, Yonsei University, Seoul, 03722, South Korea.
  • 5 Department of Medical Biotechnology, Dongguk University, Gyeonggi-do, 10326, South Korea.
  • 6 Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangwon-do, 25451, South Korea.
  • 7 BioActs, Incheon, 21666, South Korea.
PMID: 32233096 DOI: 10.1002/anie.202002574
Abstract

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.

Keywords

aggregation; amyloid β-peptides; fluorescence; high-throughput screening; oligomers.

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