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

Abstract

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.

Functional studies of Drosophilazinc transporters reveal the mechanism for dietary zinc absorption and regulation

“…The MtnB- eYFP fluorescence signal was enhanced in dZip1 -overexpressing larvae at the midgut constriction (Figure 3A), indicating excessive zinc accumulation in the cytosol of these cells. Consistent with the MtnB- eYFP fluorescence result, semi-quantitative reverse transcriptase (RT)-PCR also showed that both MtnB and MtnC were induced in flies with ubiquitous dZip1 overexpression (Figure 3B) [50], and these flies displayed specific sensitivity to dietary overload of zinc, but not to dietary overload of copper or iron (Figure 3E). Zinc accumulation, as detected by the zinc indicator Zinpyr-1, was also evident when dZip1 was expressed in Chinese hamster ovary (CHO) cells (Figure 3D).…”

Zinc homeostasis and neurodegenerative disorders

“…Recent studies published by Zhang et al (2010) showed significant increases of ZnT-1, ZnT-3, ZnT-4, ZnT-6, and ZnT-7 in the hippocampus and neocortex of APPswe/PS1dE9 transgenic mice which corresponding to a form of early onset AD. Lang et al (2012) in turn demonstrated that over-expression of Drosophila homolog of human Zip1 results in zinc accumulation in Aβ42–expressing fly brains and that inhibition of Zip1 expression induces a reduction of Aβ42 fibril deposits and improves cognition (Lang et al, 2012). …”

Drosophila melanogaster as a model organism for Alzheimer’s disease

“…Furthermore, genetic inhibition of two copper-importers (Ctr1C and Ctr1B) ameliorated Aß42-induced neurodegenerative phenotypes while lowering copper load in the fly brain [58]. A study focusing on zinc as another redox active metal and its modulation of Aβ42-induced phenotypes basically showed the same [59]. Genetic downregulation of the expression of the zinc importer dZip1 consistently suppressed Aβ42-induced brain vacuolization, locomotor defects and reduced lifespan, while overexpression had the opposite effect [59].…”