Genetic Inhibition of Solute-Linked Carrier 39 Family Transporter 1 Ameliorates A beta Pathology in a Drosophila Model of Alzheimer's Disease

Lang, M. L., Wang, L., Fan, Q. W., Xiao, G. R., Wang, X. X., Zhong, Y., Zhou, B. (2012) Genetic Inhibition of Solute-Linked Carrier 39 Family Transporter 1 Ameliorates A beta Pathology in a Drosophila Model of Alzheimer's Disease. PLoS Genetics, 8 (4). pp. 623-639. ISSN 1553-7390

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URL: http://www.ncbi.nlm.nih.gov/pubmed/22570624
DOI: 10.1371/journal.pgen.1002683

Abstract

The aggregation or oligomerization of amyloid-beta (A beta) peptide is thought to be the primary causative event in pathogenesis of Alzheimer's disease (AD). Considerable in vitro evidence indicates that the aggregation/oligomerization of A beta 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 A beta 42-expressing flies, and Zn homeostasis could be modulated by forcible dZip1 expression changes. An array of phenotypes associated with A beta expression could be modified by altering dZip1 expression. Importantly, A beta 42 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 A beta 42-transgenic lies. These findings suggest that zinc contributes significantly to the A beta pathology, and manipulation of zinc transporters in AD brains may provide a novel therapeutic strategy.

Item Type: Paper
Uncontrolled Keywords: amyloid plaques transgenic mice zinc ions aggregation peptide copper brain imbalances memory iron
Subjects: diseases & disorders > mental disorders > delirium dementia cognitive disorders > Alzheimer's disease
diseases & disorders > mental disorders > delirium dementia cognitive disorders
diseases & disorders
organism description > animal > insect > Drosophila
organism description > animal > insect
CSHL Authors:
Communities: CSHL labs > Zhong lab
Depositing User: Matt Covey
Date Deposited: 30 Jan 2013 17:09
Last Modified: 30 May 2014 16:51
PMCID: PMC3343105
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26985

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