Abstract

Both genetic and pathological studies strongly implicate microglia in the development and progression of AD. However, many AD risk genes and many of the key functions ascribed to microglia similarly define peripheral myeloid cells. Despite considerable prior controversy, recent lineage tracing studies have provided compelling evidence that blood monocyte derived macrophages (MDMs) can infiltrate the brain in AD mouse models. Yet, the impact of these infiltrating cells on disease progression remains unknown. Furthermore, only limited, and inconclusive evidence suggests that MDMs might similarly infiltrate the brains of AD patients. The current application will take advantage of chimeric mouse modeling to examine the impact of both peripherally and centrally derived inflammatory signals on human microglia and MDMs engrafted within the brain. Using complimentary proteomic, spatial transcriptomic, and histological approaches we will determine whether microglia and MDMs exhibit similar or differing responses to these stimuli and the subsequent impact of myeloid cells on surrounding neural and glial function. The resulting datasets will then inform the development and validation of a high resolution spatial transcriptomic approach that can be used to define the relative contributions of infiltrating macrophages and resident microglia in human AD.