Microglia, the primary immune cells and the sensor of the brain, play a pivotal role in the maintenance of brain homeostasis, but lose their functions during the course of aging and neurodegenerative diseases. There is a gap in our knowledge about how microglial function is maintained in healthy brains and is prone to dysregulation in Alzheimer’s disease (AD). Recent studies have distinguished and described the microglia phenotype in neurodegenerative diseases. However, whether this phenotype is beneficial or detrimental in the disease progression still is not understood. This application will investigate the role of neurodegenerative microglia as a potential therapeutic target in AD. We will study the role of disease-associated microglia by employing a novel mouse model created by Cure Alzheimer’s Fund, which enables us to target specifically these cells in order to restore microglia-mediated protein clearance and brain function in animal models of AD.