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Expression in Drosophila of Tandem Amyloid β Peptides Provides Insights into Links between Aggregation and Neurotoxicity
The generation and subsequent aggregation of amyloid β (Aβ) peptides play a crucial initiating role in the pathogenesis of Alzheimer disease (AD). The two main isoforms of these peptides have 40 (Aβ(40)) or 42 residues (Aβ(42)), the latter having a higher propensity to aggregate in vitro and being t...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society for Biochemistry and Molecular Biology
2012
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370257/ https://www.ncbi.nlm.nih.gov/pubmed/22461632 http://dx.doi.org/10.1074/jbc.M112.350124 |
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author | Speretta, Elena Jahn, Thomas R. Tartaglia, Gian Gaetano Favrin, Giorgio Barros, Teresa P. Imarisio, Sara Lomas, David A. Luheshi, Leila M. Crowther, Damian C. Dobson, Christopher M. |
author_facet | Speretta, Elena Jahn, Thomas R. Tartaglia, Gian Gaetano Favrin, Giorgio Barros, Teresa P. Imarisio, Sara Lomas, David A. Luheshi, Leila M. Crowther, Damian C. Dobson, Christopher M. |
author_sort | Speretta, Elena |
collection | PubMed |
description | The generation and subsequent aggregation of amyloid β (Aβ) peptides play a crucial initiating role in the pathogenesis of Alzheimer disease (AD). The two main isoforms of these peptides have 40 (Aβ(40)) or 42 residues (Aβ(42)), the latter having a higher propensity to aggregate in vitro and being the main component of the plaques observed in vivo in AD patients. We have designed a series of tandem dimeric constructs of these Aβ peptides to probe the manner in which changes in the aggregation kinetics of Aβ affect its deposition and toxicity in a Drosophila melanogaster model system. The levels of insoluble aggregates were found to be substantially elevated in flies expressing the tandem constructs of both Aβ(40) and Aβ(42) compared with the equivalent monomeric peptides, consistent with the higher effective concentration, and hence increased aggregation rate, of the peptides in the tandem repeat. A unique feature of the Aβ(42) constructs, however, is the appearance of high levels of soluble oligomeric aggregates and a corresponding dramatic increase in their in vivo toxicity. The toxic nature of the Aβ(42) peptide in vivo can therefore be attributed to the higher kinetic stability of the oligomeric intermediate states that it populates relative to those of Aβ(40) rather than simply to its higher rate of aggregation. |
format | Online Article Text |
id | pubmed-3370257 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-33702572012-06-15 Expression in Drosophila of Tandem Amyloid β Peptides Provides Insights into Links between Aggregation and Neurotoxicity Speretta, Elena Jahn, Thomas R. Tartaglia, Gian Gaetano Favrin, Giorgio Barros, Teresa P. Imarisio, Sara Lomas, David A. Luheshi, Leila M. Crowther, Damian C. Dobson, Christopher M. J Biol Chem Molecular Bases of Disease The generation and subsequent aggregation of amyloid β (Aβ) peptides play a crucial initiating role in the pathogenesis of Alzheimer disease (AD). The two main isoforms of these peptides have 40 (Aβ(40)) or 42 residues (Aβ(42)), the latter having a higher propensity to aggregate in vitro and being the main component of the plaques observed in vivo in AD patients. We have designed a series of tandem dimeric constructs of these Aβ peptides to probe the manner in which changes in the aggregation kinetics of Aβ affect its deposition and toxicity in a Drosophila melanogaster model system. The levels of insoluble aggregates were found to be substantially elevated in flies expressing the tandem constructs of both Aβ(40) and Aβ(42) compared with the equivalent monomeric peptides, consistent with the higher effective concentration, and hence increased aggregation rate, of the peptides in the tandem repeat. A unique feature of the Aβ(42) constructs, however, is the appearance of high levels of soluble oligomeric aggregates and a corresponding dramatic increase in their in vivo toxicity. The toxic nature of the Aβ(42) peptide in vivo can therefore be attributed to the higher kinetic stability of the oligomeric intermediate states that it populates relative to those of Aβ(40) rather than simply to its higher rate of aggregation. American Society for Biochemistry and Molecular Biology 2012-06-08 2012-03-29 /pmc/articles/PMC3370257/ /pubmed/22461632 http://dx.doi.org/10.1074/jbc.M112.350124 Text en © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles |
spellingShingle | Molecular Bases of Disease Speretta, Elena Jahn, Thomas R. Tartaglia, Gian Gaetano Favrin, Giorgio Barros, Teresa P. Imarisio, Sara Lomas, David A. Luheshi, Leila M. Crowther, Damian C. Dobson, Christopher M. Expression in Drosophila of Tandem Amyloid β Peptides Provides Insights into Links between Aggregation and Neurotoxicity |
title | Expression in Drosophila of Tandem Amyloid β Peptides Provides Insights into Links between Aggregation and Neurotoxicity |
title_full | Expression in Drosophila of Tandem Amyloid β Peptides Provides Insights into Links between Aggregation and Neurotoxicity |
title_fullStr | Expression in Drosophila of Tandem Amyloid β Peptides Provides Insights into Links between Aggregation and Neurotoxicity |
title_full_unstemmed | Expression in Drosophila of Tandem Amyloid β Peptides Provides Insights into Links between Aggregation and Neurotoxicity |
title_short | Expression in Drosophila of Tandem Amyloid β Peptides Provides Insights into Links between Aggregation and Neurotoxicity |
title_sort | expression in drosophila of tandem amyloid β peptides provides insights into links between aggregation and neurotoxicity |
topic | Molecular Bases of Disease |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370257/ https://www.ncbi.nlm.nih.gov/pubmed/22461632 http://dx.doi.org/10.1074/jbc.M112.350124 |
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