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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2012
Materias:
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.
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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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