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Capping of Aβ42 Oligomers by Small Molecule Inhibitors
[Image: see text] Aβ42 peptides associate into soluble oligomers and protofibrils in the process of forming the amyloid fibrils associated with Alzheimer’s disease. The oligomers have been reported to be more toxic to neurons than fibrils, and have been targeted by a wide range of small molecule and...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical Society
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278677/ https://www.ncbi.nlm.nih.gov/pubmed/25422864 http://dx.doi.org/10.1021/bi500910b |
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author | Fu, Ziao Aucoin, Darryl Ahmed, Mahiuddin Ziliox, Martine Van Nostrand, William E. Smith, Steven O. |
author_facet | Fu, Ziao Aucoin, Darryl Ahmed, Mahiuddin Ziliox, Martine Van Nostrand, William E. Smith, Steven O. |
author_sort | Fu, Ziao |
collection | PubMed |
description | [Image: see text] Aβ42 peptides associate into soluble oligomers and protofibrils in the process of forming the amyloid fibrils associated with Alzheimer’s disease. The oligomers have been reported to be more toxic to neurons than fibrils, and have been targeted by a wide range of small molecule and peptide inhibitors. With single touch atomic force microscopy (AFM), we show that monomeric Aβ42 forms two distinct types of oligomers, low molecular weight (MW) oligomers with heights of 1–2 nm and high MW oligomers with heights of 3–5 nm. In both cases, the oligomers are disc-shaped with diameters of ∼10–15 nm. The similar diameters suggest that the low MW species stack to form the high MW oligomers. The ability of Aβ42 inhibitors to interact with these oligomers is probed using atomic force microscopy and NMR spectroscopy. We show that curcumin and resveratrol bind to the N-terminus (residues 5–20) of Aβ42 monomers and cap the height of the oligomers that are formed at 1–2 nm. A second class of inhibitors, which includes sulindac sulfide and indomethacin, exhibit very weak interactions across the Aβ42 sequence and do not block the formation of the high MW oligomers. The correlation between N-terminal interactions and capping of the height of the Aβ oligomers provides insights into the mechanism of inhibition and the pathway of Aβ aggregation. |
format | Online Article Text |
id | pubmed-4278677 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American
Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-42786772015-11-25 Capping of Aβ42 Oligomers by Small Molecule Inhibitors Fu, Ziao Aucoin, Darryl Ahmed, Mahiuddin Ziliox, Martine Van Nostrand, William E. Smith, Steven O. Biochemistry [Image: see text] Aβ42 peptides associate into soluble oligomers and protofibrils in the process of forming the amyloid fibrils associated with Alzheimer’s disease. The oligomers have been reported to be more toxic to neurons than fibrils, and have been targeted by a wide range of small molecule and peptide inhibitors. With single touch atomic force microscopy (AFM), we show that monomeric Aβ42 forms two distinct types of oligomers, low molecular weight (MW) oligomers with heights of 1–2 nm and high MW oligomers with heights of 3–5 nm. In both cases, the oligomers are disc-shaped with diameters of ∼10–15 nm. The similar diameters suggest that the low MW species stack to form the high MW oligomers. The ability of Aβ42 inhibitors to interact with these oligomers is probed using atomic force microscopy and NMR spectroscopy. We show that curcumin and resveratrol bind to the N-terminus (residues 5–20) of Aβ42 monomers and cap the height of the oligomers that are formed at 1–2 nm. A second class of inhibitors, which includes sulindac sulfide and indomethacin, exhibit very weak interactions across the Aβ42 sequence and do not block the formation of the high MW oligomers. The correlation between N-terminal interactions and capping of the height of the Aβ oligomers provides insights into the mechanism of inhibition and the pathway of Aβ aggregation. American Chemical Society 2014-11-25 2014-12-23 /pmc/articles/PMC4278677/ /pubmed/25422864 http://dx.doi.org/10.1021/bi500910b Text en Copyright © 2014 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Fu, Ziao Aucoin, Darryl Ahmed, Mahiuddin Ziliox, Martine Van Nostrand, William E. Smith, Steven O. Capping of Aβ42 Oligomers by Small Molecule Inhibitors |
title | Capping of Aβ42 Oligomers by Small Molecule
Inhibitors |
title_full | Capping of Aβ42 Oligomers by Small Molecule
Inhibitors |
title_fullStr | Capping of Aβ42 Oligomers by Small Molecule
Inhibitors |
title_full_unstemmed | Capping of Aβ42 Oligomers by Small Molecule
Inhibitors |
title_short | Capping of Aβ42 Oligomers by Small Molecule
Inhibitors |
title_sort | capping of aβ42 oligomers by small molecule
inhibitors |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278677/ https://www.ncbi.nlm.nih.gov/pubmed/25422864 http://dx.doi.org/10.1021/bi500910b |
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