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Genetic Inhibition of Solute-Linked Carrier 39 Family Transporter 1 Ameliorates Aβ Pathology in a Drosophila Model of Alzheimer's Disease
The aggregation or oligomerization of amyloid-β (Aβ) peptide is thought to be the primary causative event in the pathogenesis of Alzheimer's disease (AD). Considerable in vitro evidence indicates that the aggregation/oligomerization of Aβ is promoted in the presence of Zn; however, the function...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343105/ https://www.ncbi.nlm.nih.gov/pubmed/22570624 http://dx.doi.org/10.1371/journal.pgen.1002683 |
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author | Lang, Minglin Wang, Lei Fan, Qiangwang Xiao, Guiran Wang, Xiaoxi Zhong, Yi Zhou, Bing |
author_facet | Lang, Minglin Wang, Lei Fan, Qiangwang Xiao, Guiran Wang, Xiaoxi Zhong, Yi Zhou, Bing |
author_sort | Lang, Minglin |
collection | PubMed |
description | The aggregation or oligomerization of amyloid-β (Aβ) peptide is thought to be the primary causative event in the pathogenesis of Alzheimer's disease (AD). Considerable in vitro evidence indicates that the aggregation/oligomerization of Aβ is promoted in the presence of Zn; however, the functional role of Zn in AD pathogenesis is still not well clarified in vivo. Zn is imported into the brain mainly through the solute-linked carrier (Slc) 39 family transporters. Using a genetically tractable Drosophila model, we found that the expression of dZip1, the orthologue of human Slc39 family transporter hZip1 in Drosophila, was altered in the brains of Aβ42-expressing flies, and Zn homeostasis could be modulated by forcible dZip1 expression changes. An array of phenotypes associated with Aβ expression could be modified by altering dZip1 expression. Importantly, Aβ42 fibril deposits as well as its SDS-soluble form were dramatically reduced upon dZip1 inhibition, resulting in less neurodegeneration, significantly improved cognitive performance, and prolonged lifespan of the Aβ42-transgenic flies. These findings suggest that zinc contributes significantly to the Aβ pathology, and manipulation of zinc transporters in AD brains may provide a novel therapeutic strategy. |
format | Online Article Text |
id | pubmed-3343105 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33431052012-05-08 Genetic Inhibition of Solute-Linked Carrier 39 Family Transporter 1 Ameliorates Aβ Pathology in a Drosophila Model of Alzheimer's Disease Lang, Minglin Wang, Lei Fan, Qiangwang Xiao, Guiran Wang, Xiaoxi Zhong, Yi Zhou, Bing PLoS Genet Research Article The aggregation or oligomerization of amyloid-β (Aβ) peptide is thought to be the primary causative event in the pathogenesis of Alzheimer's disease (AD). Considerable in vitro evidence indicates that the aggregation/oligomerization of Aβ is promoted in the presence of Zn; however, the functional role of Zn in AD pathogenesis is still not well clarified in vivo. Zn is imported into the brain mainly through the solute-linked carrier (Slc) 39 family transporters. Using a genetically tractable Drosophila model, we found that the expression of dZip1, the orthologue of human Slc39 family transporter hZip1 in Drosophila, was altered in the brains of Aβ42-expressing flies, and Zn homeostasis could be modulated by forcible dZip1 expression changes. An array of phenotypes associated with Aβ expression could be modified by altering dZip1 expression. Importantly, Aβ42 fibril deposits as well as its SDS-soluble form were dramatically reduced upon dZip1 inhibition, resulting in less neurodegeneration, significantly improved cognitive performance, and prolonged lifespan of the Aβ42-transgenic flies. These findings suggest that zinc contributes significantly to the Aβ pathology, and manipulation of zinc transporters in AD brains may provide a novel therapeutic strategy. Public Library of Science 2012-04-26 /pmc/articles/PMC3343105/ /pubmed/22570624 http://dx.doi.org/10.1371/journal.pgen.1002683 Text en Lang 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 Lang, Minglin Wang, Lei Fan, Qiangwang Xiao, Guiran Wang, Xiaoxi Zhong, Yi Zhou, Bing Genetic Inhibition of Solute-Linked Carrier 39 Family Transporter 1 Ameliorates Aβ Pathology in a Drosophila Model of Alzheimer's Disease |
title | Genetic Inhibition of Solute-Linked Carrier 39 Family Transporter 1 Ameliorates Aβ Pathology in a Drosophila Model of Alzheimer's Disease |
title_full | Genetic Inhibition of Solute-Linked Carrier 39 Family Transporter 1 Ameliorates Aβ Pathology in a Drosophila Model of Alzheimer's Disease |
title_fullStr | Genetic Inhibition of Solute-Linked Carrier 39 Family Transporter 1 Ameliorates Aβ Pathology in a Drosophila Model of Alzheimer's Disease |
title_full_unstemmed | Genetic Inhibition of Solute-Linked Carrier 39 Family Transporter 1 Ameliorates Aβ Pathology in a Drosophila Model of Alzheimer's Disease |
title_short | Genetic Inhibition of Solute-Linked Carrier 39 Family Transporter 1 Ameliorates Aβ Pathology in a Drosophila Model of Alzheimer's Disease |
title_sort | genetic inhibition of solute-linked carrier 39 family transporter 1 ameliorates aβ pathology in a drosophila model of alzheimer's disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343105/ https://www.ncbi.nlm.nih.gov/pubmed/22570624 http://dx.doi.org/10.1371/journal.pgen.1002683 |
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