Recent genetic studies have demonstrated that a nonsynonimous polymorphism of the cell surface receptor TREM-Like 2 (TREML2) is protective for Alzheimer’s disease (AD)1, 2. However, the function of TREML2 and its relationship to AD remain largely unresolved. Studies proposed in this application will provide the initial characterization of the expression and function of TREML2 in the human brain in AD and normal aging. Moreover, we propose the generation and the initial characterization of Treml2–/– mice, which will provide an invaluable resource for us and other investigators in the field for future mechanistic studies. This project will provide neurologists and immunologists with valuable resources that may be crucial for understanding the pathogenesis of AD and harnessing TREML2 for new strategies of therapeutic intervention in AD.