Project Summary Alzheimer’s Disease (AD) is a common neurological disease that results in dementia and affects more than 5.7 million Americans. At a molecular level AD is characterized by the formation of β-amyloid plaques in the interneuronal space and neurofibrillary tangles within neurons. The formation of β-amyloid plaques arises due to the aggregation of the amyloid β (Aβ) peptide, and both soluble Aβ peptides and β-amyloid plaques have been linked to cytotoxicity and AD pathogenesis. Despite these clear links to AD, the normal physiological role of Aβ is incompletely understood. Recent research suggests that Aβ plays a role in the innate immune response to infection, and accordingly pathogen infection has been associated with increased levels of Aβ and the subsequent formation of β-amyloid plaques. The goal of the proposed research is to test the link between Aβ and innate immune responses using the Drosophila melanogaster-parasitoid wasp model system. In this system, Drosophila are infected by wasps and mount a genetically conserved cellular innate immune response to kill the invading parasite. Preliminary studies show that loss the Aβ precursor protein APPL blocks the production of a successful immune response, suggesting that the role of Aβ in host defense is evolutionarily conserved. Specific Aim 1 will further define the roles of Aβ, APPL and the APPL processing enzyme BACE in the innate immune response. Notably, the overexpression of human Aβ in Drosophila leads to an infection dependent autoimmune response, in which Aβ appears to target immune cells against self tissue, leading to immune induced tissue damage. Specific Aim 1 will also provide insight into the role of Aβ in the production of this self directed immune damage, including characterizing the localization of Aβ during the immune response and identifying the immune cell receptors that are responding to Aβ expression. Additionally, during infection the parasitoid wasps transfer venom proteins into the Drosophila host. This venom contains virulence factors that allow the parasite to overcome the host immune response. Two parasitoid wasp species have been identified that block the self directed immune damage mediated by Aβ expression, suggesting that they utilize venom virulence proteins that target Aβ. Specific Aim 2 will characterize this activity and identify the Aβ inhibitory proteins found in parasite venom. This proposal will provide insight into the relationship between Aβ and innate immunity and may help uncover novel targets for the treatment of AD.