Alzheimer's disease (hereafter, AD), a progressive neurodegenerative disorder, is fatal with no effective cure to date. The neurodegeneration associated with AD also coincides with accumulation of extra- cellular amyloid-beta 42 (Aß42) plaques and/or intracellular neurofibrillary tangles (NFTs). The amyloid plaques comprise of extra-cellular deposition of hydrophobic Aß42 polypeptides, and intracellular aggregation of NFTs comprising of highly phosphorylated microtubule associate protein tau. The molecular basis for Aß42 plaques accumulation and/or NFT formation mediated neurodegeneration in AD is poorly understood. Many strategies including model organisms have been devised. Drosophila melanogaster, fruit fly, with large repository of mutants, array of genetic tools, and similar genetic makeup to humans also serves as an excellent model for human diseases like AD. Drosophila can be used for high throughput genome wide-screens, and for testing and screening of therapeutic compounds. We have established transgenic fly models where we misexpress high levels of human Aß42 or human hyperphosphorylated tau polypeptides in the retinal neurons of the eye, which exhibits AD like neuropathology of progressive neuronal death. These stable transgenic lines exhibits Aß42/ tau mediated cell death in nearly 100% flies at 29oC. Our goal is to employ our Drosophila eye model to (a) identify and characterize Hippo as a genetic modifier, (b) test if alterations in Hippo activity is correlated Aß42 and/ or tau mediated neurodegeneration and look for chemical inhibitors of Aß42 plaque/ tau mediated Alzheimer's neuropathology. In a forward genetic screen, we identified highly conserved growth regulatory Hippo signaling pathway members as dominant modifier of neurodegeneration caused by accumulation of Aß42 or hyperphosphorylated tau polypeptides. We will investigate the role of Hippo signaling pathway in tau and Aß42 plaque mediated neurodegeneration. The role of Hippo signaling has been extensively studied in growth regulation but its role in neurodegeneration is relatively underexplored. The second aim is to identify biomarkers and chemical inhibitors of Hippo signaling in Aβ42 and tau mediated neurodegeneration. We will study molecular mechanisms underlying the genetic interactions of Hippo pathway components with Aß42 or tau mediated neurodegeneration. We have established a chemical screen assay using these transgenic flies. We will test the inhibitors of Hippo signaling pathway for their efficacy to block Aß42and/or tau mediated neurodegeneration. In future, we will translate these findings from flies to humans using human patient samples. These basic studies are a prerequisite to exploring and developing therapies for neurodegenerative disorders like AD for which there are no effective treatments. We can further evaluate these potential drug targets for their diagnostic or therapeutic value in the detection or treatment of neurodegenerative diseases.