In Alzheimer’s disease, abnormal aggregates of a protein called Abeta accumulate in the brain tissue in the spaces in between cells. These aggregates are believed to be toxic to the neurons and trigger changes that lead to dementia. Microglia are immune cells that patrol these spaces and take up these abnormal protein aggregates via a process called phagocytosis. Our studies as well as others’ work points to impaired phagocytosis by the microglia in brains with advanced Alzheimer’s disease, which leads to an inability to clear these abnormal protein aggregates. In this pilot proposal, we will study how impairment of phagocytosis in microglia affects other cells in the brain. We will employ genetic manipulation in mice to disable two key genes involved in phagocytosis, namely Mer and Axl, in microglia in mouse models of Alzehimer’s disease. Thereafter, we will utilize state-of-the art genetic sequencing to understand the effects of these manipulations on microglia, as well as on other brain cell types. These data will be compared with the information generated from genetic sequencing on human brain tissue from patients with Alzheimer’s disease to understand mechanisms of disease progression that are common between this animal model and human disease. Understanding these mechanisms will be critical in developing targeted therapies to prevent and/or treat Alzheimer’s disease.