Alzheimer’s disease (AD), an age related progressive neurodegenerative disorder manifests as memory loss and reduced cognitive ability. One of the hallmarks of AD is formation of the Amyloid-beta (hereafter Aβ42) plaques, which initiates oxidative stress due to impaired signaling and finally leads to the death of neurons by unknown mechanism. However the exact mechanism causing cell death is still not well understood. We misexpressed high levels of human Aβ42 protein in the developing fly retina, which mimics AD like neuropathology. In a forward genetic screen we have identified members of highly conserved Wingless (Wg) signaling pathway as modifiers of the Aβ42 mediated neurodegeneration. Furthermore, Wg protein levels are upregulated in the dying cells marked by TUNEL staining. We have demonstrated that blocking Wg signaling pathway, by misexpressing negative regulator of Wg like Shaggy kinase (sgg) or a dominant negative form of Drosophila T-cell factor (dTCFDN5) or blocking Wg transport specifically by downregulating Porcupine (using porcupineRNAi) can rescue Aβ42 mediated neurodegeneration by reducing the number of dying cells and restoring the axonal targeting from the retina to the brain. We have developed a drug feeding regimen for flies and will test if we can use chemical inhibitors to block Wg signaling in neurons expressing high levels of Aβ42 and thereby prevent neurodegeneration in the Drosophila eye. We will test antagonists and agonist of Wg signaling to determine if they can work as chemical inhibitor/modifier of Aβ42 mediated neurodegeneration. The results from our studies will be presented.