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

<div><p>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 <em>in vitro</em> 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 <em>in vivo</em>. Zn is imported into the brain mainly through the solute-linked carrier (<em>Slc</em>) 39 family transporters. Using a genetically tractable <em>Drosophila</em> model, we found that the expression of <em>dZip1</em>, the orthologue of human <em>Slc39</em> family transporter <em>hZip1</em> in <em>Drosophila</em>, was altered in the brains of Aβ42-expressing flies, and Zn homeostasis could be modulated by forcible <em>dZip1</em> expression changes. An array of phenotypes associated with Aβ expression could be modified by altering <em>dZip1</em> expression. Importantly, Aβ42 fibril deposits as well as its SDS-soluble form were dramatically reduced upon <em>dZip1</em> 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.</p>