PROJECT SUMMARY Alzheimer’s disease is the most common cause of dementia in the elderly. Recent genetic data strongly suggest that microglia-mediated innate immune activities may directly contribute to the AD mechanisms at early onset and/or developmental stage of this disease. Understanding the molecular mechanisms underpinning how microglia are functionally involved in the pathogenesis of AD is beneficial for the development of new therapeutic strategies for AD. Our long-term objective is to dissect the function of adaptor protein DAP12 in mediating complex signals and executing their functions in microglia involved in AD pathogenesis. Our preliminary data revealed a global effect of DAP12 deficiency in the brain transcriptome of tau P301S mouse, which reverses the transcriptomic changes featured in the brains of multiple AD transgenic mouse models. We further found that DAP12 deficiency increased brain tau pathology in tau P301S mice and reduced tau degradation by cultured primary microglia. Yet, DAP12 deficiency significantly decreased brain microgliosis in tau P301S mice. Therefore, we hypothesize that DAP12 plays differential roles in tau metabolism and microglia-mediated inflammation during the pathogenesis of AD. We plan to fully characterize the role of DAP12 in these two AD- relevant cellular events mediated by microglia and tau seeding/spreading. Finally we will further determine signaling pathways altered by DAP12 deficiency on cell type specific manner in tauopathy mice.