Cargando…
Aβ42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila
Aggregation of the amyloid-β-42 (Aβ42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of Aβ aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that Aβ can form several different prefibri...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2008
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2250771/ https://www.ncbi.nlm.nih.gov/pubmed/18301778 http://dx.doi.org/10.1371/journal.pone.0001703 |
_version_ | 1782151104914522112 |
---|---|
author | Iijima, Koichi Chiang, Hsueh-Cheng Hearn, Stephen A. Hakker, Inessa Gatt, Anthony Shenton, Christopher Granger, Linda Leung, Amy Iijima-Ando, Kanae Zhong, Yi |
author_facet | Iijima, Koichi Chiang, Hsueh-Cheng Hearn, Stephen A. Hakker, Inessa Gatt, Anthony Shenton, Christopher Granger, Linda Leung, Amy Iijima-Ando, Kanae Zhong, Yi |
author_sort | Iijima, Koichi |
collection | PubMed |
description | Aggregation of the amyloid-β-42 (Aβ42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of Aβ aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that Aβ can form several different prefibrillar and fibrillar aggregates and that each aggregate may confer different pathogenic effects, suggesting that manipulation of Aβ42 aggregation may not only quantitatively but also qualitatively modify brain pathology. Here, we compare the pathogenicity of human Aβ42 mutants with differing tendencies to aggregate. We examined the aggregation-prone, EOFAD-related Arctic mutation (Aβ42Arc) and an artificial mutation (Aβ42art) that is known to suppress aggregation and toxicity of Aβ42 in vitro. In the Drosophila brain, Aβ42Arc formed more oligomers and deposits than did wild type Aβ42, while Aβ42art formed fewer oligomers and deposits. The severity of locomotor dysfunction and premature death positively correlated with the aggregation tendencies of Aβ peptides. Surprisingly, however, Aβ42art caused earlier onset of memory defects than Aβ42. More remarkably, each Aβ induced qualitatively different pathologies. Aβ42Arc caused greater neuron loss than did Aβ42, while Aβ42art flies showed the strongest neurite degeneration. This pattern of degeneration coincides with the distribution of Thioflavin S-stained Aβ aggregates: Aβ42Arc formed large deposits in the cell body, Aβ42art accumulated preferentially in the neurites, while Aβ42 accumulated in both locations. Our results demonstrate that manipulation of the aggregation propensity of Aβ42 does not simply change the level of toxicity, but can also result in qualitative shifts in the pathology induced in vivo. |
format | Text |
id | pubmed-2250771 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-22507712008-02-27 Aβ42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila Iijima, Koichi Chiang, Hsueh-Cheng Hearn, Stephen A. Hakker, Inessa Gatt, Anthony Shenton, Christopher Granger, Linda Leung, Amy Iijima-Ando, Kanae Zhong, Yi PLoS One Research Article Aggregation of the amyloid-β-42 (Aβ42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of Aβ aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that Aβ can form several different prefibrillar and fibrillar aggregates and that each aggregate may confer different pathogenic effects, suggesting that manipulation of Aβ42 aggregation may not only quantitatively but also qualitatively modify brain pathology. Here, we compare the pathogenicity of human Aβ42 mutants with differing tendencies to aggregate. We examined the aggregation-prone, EOFAD-related Arctic mutation (Aβ42Arc) and an artificial mutation (Aβ42art) that is known to suppress aggregation and toxicity of Aβ42 in vitro. In the Drosophila brain, Aβ42Arc formed more oligomers and deposits than did wild type Aβ42, while Aβ42art formed fewer oligomers and deposits. The severity of locomotor dysfunction and premature death positively correlated with the aggregation tendencies of Aβ peptides. Surprisingly, however, Aβ42art caused earlier onset of memory defects than Aβ42. More remarkably, each Aβ induced qualitatively different pathologies. Aβ42Arc caused greater neuron loss than did Aβ42, while Aβ42art flies showed the strongest neurite degeneration. This pattern of degeneration coincides with the distribution of Thioflavin S-stained Aβ aggregates: Aβ42Arc formed large deposits in the cell body, Aβ42art accumulated preferentially in the neurites, while Aβ42 accumulated in both locations. Our results demonstrate that manipulation of the aggregation propensity of Aβ42 does not simply change the level of toxicity, but can also result in qualitative shifts in the pathology induced in vivo. Public Library of Science 2008-02-27 /pmc/articles/PMC2250771/ /pubmed/18301778 http://dx.doi.org/10.1371/journal.pone.0001703 Text en Iijima 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 Iijima, Koichi Chiang, Hsueh-Cheng Hearn, Stephen A. Hakker, Inessa Gatt, Anthony Shenton, Christopher Granger, Linda Leung, Amy Iijima-Ando, Kanae Zhong, Yi Aβ42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila |
title | Aβ42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila
|
title_full | Aβ42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila
|
title_fullStr | Aβ42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila
|
title_full_unstemmed | Aβ42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila
|
title_short | Aβ42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila
|
title_sort | aβ42 mutants with different aggregation profiles induce distinct pathologies in drosophila |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2250771/ https://www.ncbi.nlm.nih.gov/pubmed/18301778 http://dx.doi.org/10.1371/journal.pone.0001703 |
work_keys_str_mv | AT iijimakoichi ab42mutantswithdifferentaggregationprofilesinducedistinctpathologiesindrosophila AT chianghsuehcheng ab42mutantswithdifferentaggregationprofilesinducedistinctpathologiesindrosophila AT hearnstephena ab42mutantswithdifferentaggregationprofilesinducedistinctpathologiesindrosophila AT hakkerinessa ab42mutantswithdifferentaggregationprofilesinducedistinctpathologiesindrosophila AT gattanthony ab42mutantswithdifferentaggregationprofilesinducedistinctpathologiesindrosophila AT shentonchristopher ab42mutantswithdifferentaggregationprofilesinducedistinctpathologiesindrosophila AT grangerlinda ab42mutantswithdifferentaggregationprofilesinducedistinctpathologiesindrosophila AT leungamy ab42mutantswithdifferentaggregationprofilesinducedistinctpathologiesindrosophila AT iijimaandokanae ab42mutantswithdifferentaggregationprofilesinducedistinctpathologiesindrosophila AT zhongyi ab42mutantswithdifferentaggregationprofilesinducedistinctpathologiesindrosophila |