Cargando…
Aryloxypropanolamine targets amyloid aggregates and reverses Alzheimer-like phenotypes in Alzheimer mouse models
BACKGROUND: Aggregated amyloid-β (Aβ) is considered a pathogenic initiator of Alzheimer’s disease (AD), in strong association with tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, and cognitive decline. As the removal of amyloid burden from AD patient brains by antibodies has shown...
Autores principales: | , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9706920/ https://www.ncbi.nlm.nih.gov/pubmed/36443837 http://dx.doi.org/10.1186/s13195-022-01112-6 |
_version_ | 1784840604081979392 |
---|---|
author | Lee, Hee Yang Yoon, Soljee Lee, Jeong Hwa Park, Keunwan Jung, Youngeun Cho, Illhwan Lee, Donghee Shin, Jisu Kim, Kyeonghwan Kim, Sunmi Kim, Jimin Kim, Koeun Han, Seung Hoon Kim, Seong Muk Kim, Hye Ju Kim, Hye Yun Kim, Ikyon Kim, Young Soo |
author_facet | Lee, Hee Yang Yoon, Soljee Lee, Jeong Hwa Park, Keunwan Jung, Youngeun Cho, Illhwan Lee, Donghee Shin, Jisu Kim, Kyeonghwan Kim, Sunmi Kim, Jimin Kim, Koeun Han, Seung Hoon Kim, Seong Muk Kim, Hye Ju Kim, Hye Yun Kim, Ikyon Kim, Young Soo |
author_sort | Lee, Hee Yang |
collection | PubMed |
description | BACKGROUND: Aggregated amyloid-β (Aβ) is considered a pathogenic initiator of Alzheimer’s disease (AD), in strong association with tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, and cognitive decline. As the removal of amyloid burden from AD patient brains by antibodies has shown therapeutic potential, the development of small molecule drugs inducing chemical dissociation and clearance of Aβ is compelling as a therapeutic strategy. In this study, we synthesized and screened aryloxypropanolamine derivatives and identified 1-(3-(2,4-di-tert-pentylphenoxy)-2-hydroxypropyl)pyrrolidin-1-ium chloride, YIAD002, as a strong dissociator of Aβ aggregates. METHODS: The dissociative activity of aryloxypropanolamine derivatives against Aβ aggregates were evaluated through in vitro assays. Immunohistochemical staining, immunoblot assays, and the Morris water maze were used to assess the anti-Alzheimer potential in YIAD002-treated 5XFAD and transgenic APP/PS1 mice. Target-ligand interaction mechanism was characterized via a combination of peptide mapping, fluorescence dissociation assays, and constrained docking simulations. RESULTS: Among 11 aryloxypropanolamine derivatives, YIAD002 exerted strongest dissociative activity against β-sheet-rich Aβ aggregates. Upon oral administration, YIAD002 substantially reduced amyloid burden and accordingly, improved cognitive performance in the Morris water maze and attenuated major pathological hallmarks of AD including tauopathy, neuroinflammation, and synaptic protein loss. Mechanism studies suggest that YIAD002 interferes with intermolecular β-sheet fibrillation by directly interacting with KLVFFA and IGLMVG domains of Aβ. In addition, YIAD002 was found to possess dissociative activity against aggregates of pyroglutamate-modified Aβ and tau. CONCLUSIONS: Collectively, our results evince the potential of chemical-driven dissociation of Aβ aggregates by aryloxypropanolamines as a therapeutic modality of the amyloid clearance approach. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-022-01112-6. |
format | Online Article Text |
id | pubmed-9706920 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-97069202022-11-30 Aryloxypropanolamine targets amyloid aggregates and reverses Alzheimer-like phenotypes in Alzheimer mouse models Lee, Hee Yang Yoon, Soljee Lee, Jeong Hwa Park, Keunwan Jung, Youngeun Cho, Illhwan Lee, Donghee Shin, Jisu Kim, Kyeonghwan Kim, Sunmi Kim, Jimin Kim, Koeun Han, Seung Hoon Kim, Seong Muk Kim, Hye Ju Kim, Hye Yun Kim, Ikyon Kim, Young Soo Alzheimers Res Ther Research BACKGROUND: Aggregated amyloid-β (Aβ) is considered a pathogenic initiator of Alzheimer’s disease (AD), in strong association with tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, and cognitive decline. As the removal of amyloid burden from AD patient brains by antibodies has shown therapeutic potential, the development of small molecule drugs inducing chemical dissociation and clearance of Aβ is compelling as a therapeutic strategy. In this study, we synthesized and screened aryloxypropanolamine derivatives and identified 1-(3-(2,4-di-tert-pentylphenoxy)-2-hydroxypropyl)pyrrolidin-1-ium chloride, YIAD002, as a strong dissociator of Aβ aggregates. METHODS: The dissociative activity of aryloxypropanolamine derivatives against Aβ aggregates were evaluated through in vitro assays. Immunohistochemical staining, immunoblot assays, and the Morris water maze were used to assess the anti-Alzheimer potential in YIAD002-treated 5XFAD and transgenic APP/PS1 mice. Target-ligand interaction mechanism was characterized via a combination of peptide mapping, fluorescence dissociation assays, and constrained docking simulations. RESULTS: Among 11 aryloxypropanolamine derivatives, YIAD002 exerted strongest dissociative activity against β-sheet-rich Aβ aggregates. Upon oral administration, YIAD002 substantially reduced amyloid burden and accordingly, improved cognitive performance in the Morris water maze and attenuated major pathological hallmarks of AD including tauopathy, neuroinflammation, and synaptic protein loss. Mechanism studies suggest that YIAD002 interferes with intermolecular β-sheet fibrillation by directly interacting with KLVFFA and IGLMVG domains of Aβ. In addition, YIAD002 was found to possess dissociative activity against aggregates of pyroglutamate-modified Aβ and tau. CONCLUSIONS: Collectively, our results evince the potential of chemical-driven dissociation of Aβ aggregates by aryloxypropanolamines as a therapeutic modality of the amyloid clearance approach. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-022-01112-6. BioMed Central 2022-11-29 /pmc/articles/PMC9706920/ /pubmed/36443837 http://dx.doi.org/10.1186/s13195-022-01112-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Lee, Hee Yang Yoon, Soljee Lee, Jeong Hwa Park, Keunwan Jung, Youngeun Cho, Illhwan Lee, Donghee Shin, Jisu Kim, Kyeonghwan Kim, Sunmi Kim, Jimin Kim, Koeun Han, Seung Hoon Kim, Seong Muk Kim, Hye Ju Kim, Hye Yun Kim, Ikyon Kim, Young Soo Aryloxypropanolamine targets amyloid aggregates and reverses Alzheimer-like phenotypes in Alzheimer mouse models |
title | Aryloxypropanolamine targets amyloid aggregates and reverses Alzheimer-like phenotypes in Alzheimer mouse models |
title_full | Aryloxypropanolamine targets amyloid aggregates and reverses Alzheimer-like phenotypes in Alzheimer mouse models |
title_fullStr | Aryloxypropanolamine targets amyloid aggregates and reverses Alzheimer-like phenotypes in Alzheimer mouse models |
title_full_unstemmed | Aryloxypropanolamine targets amyloid aggregates and reverses Alzheimer-like phenotypes in Alzheimer mouse models |
title_short | Aryloxypropanolamine targets amyloid aggregates and reverses Alzheimer-like phenotypes in Alzheimer mouse models |
title_sort | aryloxypropanolamine targets amyloid aggregates and reverses alzheimer-like phenotypes in alzheimer mouse models |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9706920/ https://www.ncbi.nlm.nih.gov/pubmed/36443837 http://dx.doi.org/10.1186/s13195-022-01112-6 |
work_keys_str_mv | AT leeheeyang aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT yoonsoljee aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT leejeonghwa aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT parkkeunwan aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT jungyoungeun aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT choillhwan aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT leedonghee aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT shinjisu aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT kimkyeonghwan aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT kimsunmi aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT kimjimin aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT kimkoeun aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT hanseunghoon aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT kimseongmuk aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT kimhyeju aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT kimhyeyun aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT kimikyon aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels AT kimyoungsoo aryloxypropanolaminetargetsamyloidaggregatesandreversesalzheimerlikephenotypesinalzheimermousemodels |