The mechanism by which aggregates of the β-amyloid peptide (Aβ) mediate their toxicity is uncertain. We show here that the expression of the 42-amino-acid isoform of Aβ (Aβ1–42) changes the expression of genes involved in oxidative stress in a Drosophila model of Alzheimer’s disease. A subsequent genetic screen confirmed the importance of oxidative stress and a molecular dissection of the steps in the cellular metabolism of reactive oxygen species revealed that the iron-binding protein ferritin and the H2O2 scavenger catalase are the most potent suppressors of the toxicity of wild-type and Arctic (E22G) Aβ1–42. Likewise, treatment with the iron-binding compound clioquinol increased the lifespan of flies expressing Arctic Aβ1–42. The effect of iron appears to be mediated by oxidative stress as ferritin heavy chain co-expression reduced carbonyl levels in Aβ1–42 flies by 65% and restored the survival and locomotion function to normal. This was achieved despite the presence of elevated levels of the Aβ1–42. Taken together, our data show that oxidative stress, probably mediated by the hydroxyl radical and generated by the Fenton reaction, is essential for Aβ1–42 toxicity in vivo and provide strong support for Alzheimer’s disease therapies based on metal chelation.

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SummaryAn in vivo model of apoptosis: linking cell behaviours and caspase substrates in embryos lacking DIAP1

During the development of the Drosophila embryonic epidermis, the secreted Wingless protein initially spreads symmetrically from its source. At later stages, Wingless becomes asymmetrically distributed in a Hedgehog-dependent manner, to control the patterning of the embryonic epidermis. When Wingless is misexpressed in engrailed cells in hedgehog heterozygous mutant embryos, larvae show a dominant phenotype consisting of patches of naked cuticle in denticle belts. This dose-sensitive phenotype is a direct consequence of a change in Wg protein distribution. We used this phenotype to carry out a screen for identifying genes regulating Wingless distribution or transport in the embryonic epidermis. Using a third chromosome deficiency collection, we found several genomic regions that showed a dominant interaction. After using a secondary screen to test for mutants and smaller deficiencies, we identified three interacting genes: dally, notum, and brahma. We confirmed that dally, as well as its homolog dally-like, and notum affect Wingless distribution in the embryonic epidermis, directly or indirectly. Thus, our assay can be used effectively to screen for genes regulating Wingless distribution or transport. S ECRETED signaling molecules play an essential role distribution (Bellaiche et al. 1998;Takei et al. 2003; Han et al. 2004a,b). in patterning developing metazoans. Work from reGradient formation also depends upon the mechacent years shows that the signaling activity of these molenism by which signaling ligands move in the plane of cules is tightly regulated (Freeman 2000). Among variepithelia. It is not yet clear what these mechanisms are, ous levels of regulation, controlling the distribution of but two main modes of transport have been proposed ligands in a field of cells is necessary to establish stable (reviewed by Vincent and Dubois 2002; Gonzalezgradients that robustly pattern developing tissues (VinGaitan 2003): (1) facilitated diffusion, where ligands cent and Dubois 2002). The distribution of ligands diffuse within the extracellular space, and this diffusion could conceivably be influenced by many factors, includis modulated by cell-surface receptors, and (2) transing the concentration of receptors, the composition of cytosis, where ligands are transported along the plane the extracellular matrix, or the rate of recycling and of the epithelium by repeated cycles of endocytosis and degradation of the ligand following internalization. The recycling to the cell surface. best-documented case is the regulation of ligand distriIn this study, we searched for genes that influence bution by receptors. For example, in Drosophila, Hedgethe distribution or transport of the signaling ligand hog (Hh) range of action is regulated by its receptor Wingless (Wg), the homolog of vertebrate Wnt-1 in DroPatched: if the Hh-binding domain of Patched is musophila. In the embryonic epidermis, Wg acts at a short tated, the spread of Hh is extended in the wing imaginal range to regulate the activity of target genes, wherea...