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Structure-Based Peptide Design to Modulate Amyloid Beta Aggregation and Reduce Cytotoxicity
The deposition of Aβ peptide in the brain is the key event in Alzheimer disease progression. Therefore, the prevention of Aβ self assembly into disease-associated oligomers is a logical strategy for treatment. π stacking is known to provide structural stability to many amyloids; two phenylalanine re...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466325/ https://www.ncbi.nlm.nih.gov/pubmed/26070139 http://dx.doi.org/10.1371/journal.pone.0129087 |
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author | Kumar, Jitendra Namsechi, Risa Sim, Valerie L. |
author_facet | Kumar, Jitendra Namsechi, Risa Sim, Valerie L. |
author_sort | Kumar, Jitendra |
collection | PubMed |
description | The deposition of Aβ peptide in the brain is the key event in Alzheimer disease progression. Therefore, the prevention of Aβ self assembly into disease-associated oligomers is a logical strategy for treatment. π stacking is known to provide structural stability to many amyloids; two phenylalanine residues within the Aβ 14–23 self recognition element are in such an arrangement in many solved structures. Therefore, we targeted this structural stacking by substituting these two phenylalanine residues with their D-enantiomers. The resulting peptides were able to modulate Aβ aggregation in vitro and reduce Aβ cytotoxicity in primary neuronal cultures. Using kinetic analysis of fibril formation, electron microscopy and dynamic light scattering characterization of oligomer size distributions, we demonstrate that, in addition to altering fibril structural characteristics, these peptides can induce the formation of larger amorphous aggregates which are protective against toxic oligomers, possibly because they are able to sequester the toxic oligomers during co-incubation. Alternatively, they may alter the surface structure of the oligomers such that they can no longer interact with cells to induce toxic pathways. |
format | Online Article Text |
id | pubmed-4466325 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44663252015-06-22 Structure-Based Peptide Design to Modulate Amyloid Beta Aggregation and Reduce Cytotoxicity Kumar, Jitendra Namsechi, Risa Sim, Valerie L. PLoS One Research Article The deposition of Aβ peptide in the brain is the key event in Alzheimer disease progression. Therefore, the prevention of Aβ self assembly into disease-associated oligomers is a logical strategy for treatment. π stacking is known to provide structural stability to many amyloids; two phenylalanine residues within the Aβ 14–23 self recognition element are in such an arrangement in many solved structures. Therefore, we targeted this structural stacking by substituting these two phenylalanine residues with their D-enantiomers. The resulting peptides were able to modulate Aβ aggregation in vitro and reduce Aβ cytotoxicity in primary neuronal cultures. Using kinetic analysis of fibril formation, electron microscopy and dynamic light scattering characterization of oligomer size distributions, we demonstrate that, in addition to altering fibril structural characteristics, these peptides can induce the formation of larger amorphous aggregates which are protective against toxic oligomers, possibly because they are able to sequester the toxic oligomers during co-incubation. Alternatively, they may alter the surface structure of the oligomers such that they can no longer interact with cells to induce toxic pathways. Public Library of Science 2015-06-12 /pmc/articles/PMC4466325/ /pubmed/26070139 http://dx.doi.org/10.1371/journal.pone.0129087 Text en © 2015 Kumar et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Kumar, Jitendra Namsechi, Risa Sim, Valerie L. Structure-Based Peptide Design to Modulate Amyloid Beta Aggregation and Reduce Cytotoxicity |
title | Structure-Based Peptide Design to Modulate Amyloid Beta Aggregation and Reduce Cytotoxicity |
title_full | Structure-Based Peptide Design to Modulate Amyloid Beta Aggregation and Reduce Cytotoxicity |
title_fullStr | Structure-Based Peptide Design to Modulate Amyloid Beta Aggregation and Reduce Cytotoxicity |
title_full_unstemmed | Structure-Based Peptide Design to Modulate Amyloid Beta Aggregation and Reduce Cytotoxicity |
title_short | Structure-Based Peptide Design to Modulate Amyloid Beta Aggregation and Reduce Cytotoxicity |
title_sort | structure-based peptide design to modulate amyloid beta aggregation and reduce cytotoxicity |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466325/ https://www.ncbi.nlm.nih.gov/pubmed/26070139 http://dx.doi.org/10.1371/journal.pone.0129087 |
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