Project Summary/Abstract Recent human genetics studies of Alzheimer’s disease have revealed that many risk genes are primarily expressed in microglia. Microglia promote clearance of amyloid β (Aβ) through phagocytosis and regulate brain’s immunity by secreting cytokines and chemokines in the context of Alzheimer’s disease. Because there have been numerous in vitro studies suggesting protective as well as detrimental effects of different types of microglia in Alzheimer’s disease, how microglial Alzheimer’s disease risk genes regulate the function of these cells still remain elusive. To this end, determining the functional consequences of these genetic risk factors in Alzheimer’s disease, particularly in microglia, can provide invaluable insight into the pathobiology of the disease. In a recent large scale genome-wide analysis study, a rare coding variant was identified in Abelson interactor family member 3 (ABI3) gene and this variant is associated with increased risk of late-onset Alzheimer’s disease (LOAD). ABI3 is highly expressed in multiple myeloid cell types in the brain, spleen, and blood. ABI3 is a component of WAVE2 complex, a complex that regulates actin cytoskeleton organization. This complex is involved in cytokinesis, migration, endocytosis, and phagocytosis. Here, we propose to generate Abi3 conditional knock-out mouse model. Generation of Abi3-floxed (Abi3fl/fl) mouse model will enable us and the wider research community to dissect out the cell-type specific role of Abi3 under the homeostatic and pathological conditions.