Amyloid Against Amyloid: Dimeric Amyloid Fragment Ameliorates Cognitive Impairments by Direct Clearance of Oligomers and Plaques

Hee Yang Lee, Seungyeop Baek, Minhae Cha, Seung Hoon Yang, Illhwan Cho, Heewon Shin, Sejin Lee, Hye Yun Kim, Songmin Lee, Jisu Shin, Donghee Lee, Kyeonghwan Kim, In Wook Park, Soljee Yoon, Jiyoon Kim, Seong Jeong Park, Seong Muk Kim, Ko Eun Kim, Hye Ju Kim, Min Seok OhGwan Ho Lee, Byung Yong Yu, Priyadharshini Kannan, Keunwan Park, Young Soo Kim

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Amyloid-β (Aβ) in the form of neurotoxic aggregates is regarded as the main pathological initiator and key therapeutic target of Alzheimer's disease. However, anti-Aβ drug development has been impeded by the lack of a target needed for structure-based drug design and low permeability of the blood–brain barrier (BBB). An attractive therapeutic strategy is the development of amyloid-based anti-Aβ peptidomimetics that exploit the self-assembling nature of Aβ and penetrate the BBB. Herein, we designed a dimeric peptide drug candidate based on the N-terminal fragment of Aβ, DAB, found to cross the BBB and solubilize Aβ oligomers and fibrils. Administration of DAB reduced amyloid burden in 5XFAD mice, and downregulated neuroinflammation and prevented memory impairment in the Y-maze test. Peptide mapping assays and molecular docking studies were utilized to elucidate DAB-Aβ interaction. To further understand the active regions of DAB, we assessed the dissociative activity of DAB with sequence modifications.

Original languageEnglish
Article numbere202210209
JournalAngewandte Chemie - International Edition
Volume62
Issue number7
DOIs
Publication statusPublished - 2023 Feb 6

Bibliographical note

Publisher Copyright:
© 2022 Wiley-VCH GmbH.

All Science Journal Classification (ASJC) codes

  • Catalysis
  • General Chemistry

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