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

Jinny Claire Lee, Hye Yun Kim, Sejin Lee, Jisu Shin, Hyunjin Vincent Kim, Kyeonghwan Kim, Seungyeop Baek, Donghee Lee, Hanna Jeon, Da Won Kim, Seung Hoon Yang, Gyoonhee Han, Keunwan Park, Jaeho Choi, Jinwoo Park, Jason A. Moss, Kim D. Janda, Young Soo Kim

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)11491-11500
Number of pages10
JournalAngewandte Chemie - International Edition
Volume59
Issue number28
DOIs
Publication statusPublished - 2020 Jul 6

Bibliographical note

Funding Information:
All images are created by the authors of this manuscript. All experimental and animal protocols were approved by Yonsei University. This work was supported by Korea Health Industry Development Institute (KHIDI, HI18C0836), National Research Foundation of Korea (NRF-2018R1A6A1A03023718, NRF-2018R1D1A1B07048857, and NRF-2018M3C7A1021858), Yonsei University (2018-22-0022), KIST (2Z05620 and 2E29562), and POSCO TJ Foundation (POSCO Science Fellowship).

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)

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