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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...

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Autores principales: Lang, Minglin, Wang, Lei, Fan, Qiangwang, Xiao, Guiran, Wang, Xiaoxi, Zhong, Yi, Zhou, Bing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
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.
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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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