Microglia are specialized cells that play critical roles in brain development, immune defense, and neuronal plasticity. Importantly, microglia also profoundly influence the development and progression of many of the most common neurological disorders including Alzheimer’s disease, stroke, Parkinson’s disease, traumatic brain injury, and autism. As the resident immune cell of the brain, Microglia inherently migrate toward areas of injury and pathology and may therefore also represent an excellent candidate for cell transplantation based therapies. Despite these important functions, methods to generate microglia from pluripotent human stem cells have yet to be reported. Our goal is to therefore develop a new and highly robust approach to generate microglia from renewable human pluripotent stem cell sources. By developing such an approach, researchers can use these cells to understand the biology of microglia and their role in these various diseases. During the first year of funding our collaborative team has made excellent progress towards our goals. For example, we have developed new ‘reporter’ cell lines to help inform and guide our differentiation approach. We have also successfully developed a ‘fully-defined’ protocol for generating human microglia that uses standard medias and growth factors to generate large numbers of microglia. Importantly, unbiased genetic analysis of these cells demonstrates that they are extremely similar to brain-derived human microglia. These stem cell-derived microglia also respond to stimuli and exhibit characteristic features equivalent to human microglia in several functional assays. As our studies continue, we aim to further refine our differentiation approach and to then test the utility of stem cell-derived microglia to study important questions about the genetics and causes of Alzheimer’s disease (AD). In particular we will focus on a gene called CD33 that has been implicated in AD. This gene is thought to influence the clearance of beta-amyloid, a key protein involved in AD pathogenesis, and yet one cannot study CD33 effectively using existing mouse models of AD as the human version of this gene is unique.