Project Summary Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder which is the most common cause of severe dementia in elderly populations. Currently, there are no approved therapies which combat the mechanisms behind AD, highlighting the need to develop more, effective treatments. AD is classically characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), and brain-wide neuroinflammation. To successfully create therapies treating AD, the mechanisms behind these pathological hallmarks must be better understood. Recently, genome wide association studies (GWAS) have implicated many myeloid genes in the modulation of AD. In the central nervous system, microglia are the primary resident myeloid cells, thus, suggesting microglia are involved in AD. What is currently unknown, however, is whether microglial involvement in AD is helpful or harmful. Microglial ablation studies and global microglial gene knockout studies show conflicting results, possibly because these studies either globally alter gene transcription, or target all microglia when multiple subsets of microglia exist in AD. To date, it has not been possible to selectively target these discrete microglial populations to determine their relative roles and functions. To that end, we have developed two approaches to selectively target and modulate plaque associated microglia while leaving non-plaque associated microglia unaffected. Thus, I propose to 1) Determine the contribution of plaque associated microglia to the pathogenesis of AD through a novel, inducible destabilized cre-lox mouse line targeting the gene responsible for the microglial response to Aβ plaques, TREM2, and 2) Show proof of principle in being able to pharmacologically alter the morphological and transcriptional profile of plaque associated microglia through systemic administration of polyamidoamine hydroxyl dendrimers. Collectively, this proposal will elucidate the role of plaque associated microglia in AD and showcase a potential therapeutic treatment for these cells, leading to a clearer understanding of the role of microglia in AD outcomes.