Convergence of myeloid susceptibility protein function in Alzheimer?s disease 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.
This project is of direct relevance to Alzheimer?s disease, as we are studying proteins that are genetically associated with Alzheimer?s disease. We will be examining the state of these associated proteins in microglia from individuals with Alzheimer?s disease. Our data will potentially provide a mechanistic answer of how the genetically associated proteins functions in the innate immune system and in doing so, increases an individual?s risk of developing Alzheimer?s disease.
