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.
|Journal||Angewandte Chemie - International Edition|
|Publication status||Published - 2023 Feb 6|
Bibliographical noteFunding Information:
This research was supported by the Korea Health Technology R&D Project (Grant Number: HU21C0161, Y.K.) through the Korea Health Industry Development Institute (KHIDI) and Korea Dementia Research Center (KDRC), and Mid‐Career Researcher Program (Grant Number: NRF‐2021R1A2C2093916, Y.K.; NRF‐2021R1A2C1013247, H.K.), and Basic Science Research Program (Grant Number: NRF‐2018R1A6A1A03023718, Y.K. and H.K.) through the National Research Foundation of Korea (NRF), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea. This research was also supported by Amyloid Solution, POSCO Science Fellowship of POSCO TJ Park Foundation, and Korea Institute of Science and Technology intramural research grant (K.P.).
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