PIs: Bradshaw, Elizabeth M., Ph.D. Title: Convergence of myeloid susceptibility protein function in Alzheimer’s disease Project Summary/Abstract Alzheimer’s disease is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia. Genome-wide association studies and sequencing studies have identified novel Alzheimer’s disease susceptibility loci. Interestingly the associated genes at several of these loci implicate the immune system in late-onset Alzheimer’s disease, specifically the innate immune system. However, how the majority of the proteins derived from these genetically associated loci actually function in immune cells is still unknown, especially in the context of Alzheimer’s disease. We have identified eight genetically associated proteins, which may be working together in a tyrosine phosphorylation signaling pathway in innate immune cells. For this application, we propose a multifaceted approach to 1) identify the interacting proteins of these eight Alzheimer’s disease genetically associated proteins, which we believe function together in microglia, and for which we already have strong supporting evidence of a shared pathway 2) validate that the proteins are phosphorylated and that the interactions occur in situ in the Alzheimer’s disease brain, and finally 3) Dissect the signaling pathway in vitro to understand functional outcomes and pinpoint intervention points.