Inflammation contributes to the development and progression of virtually every human disease. While the brain is considered immune privileged, a growing body of evidence has shown that peripheral inflammation can influence the development of many neurological disorders, including Parkinson’s disease, multiple sclerosis, frontotemporal dementia, and Alzheimer’s disease (AD). Yet the mechanisms and cell types that mediate these effects remain unclear. To examine these important questions, our Neuroimmune Consortium has brought together researchers with a broad array of expertise to pursue a set of highly collaborative and complementary studies. In the current project, we will take advantage of chimeric mouse modeling to examine the effects of peripheral inflammation on human microglia and monocytes within the brain. This approach will allow us to determine the effects of peripherally derived inflammatory signals on both brain-resident and brain-infiltrating immune cells while also studying the functional genetics and biology of human cells. Using “spatial genomic” approaches, we also will examine the interactions between engrafted human immune cells and other key cell types in the brain to determine the impact of peripheral inflammation on AD pathology and neuronal function.