Targeting microglia to alleviate Alzheimer’s Disease pathobiology Summary Alzheimer’s disease (AD) is the most common cause of age-related dementia leading to irreversible neurodegeneration and cognitive decline with no cure or effective preventive measures. Autophagy is a conserved, cell response found in all eukaryotic cells. Several studies in AD showed that autophagy activity is compromised in neuronal cells and suggested that this leads to reduced clearance of amyloid-β (Aβ) and neurotoxicity. Few reports examined autophagy activity in the AD brain and suggested that autophagy is dysfunctional in neurons, however, the contribution of autophagy in microglia, the immune cell of the brain, is unclear. Our newly generated data that was recently published show that autophagy is impaired in adult microglia from AD mice. More importantly, we found that a specific microRNA (miRNA), that targets several autophagy molecules, is upregulated in the brain of AD patients when compared to non-AD individuals, as well as in the brain and microglia-derived from an AD mouse model. Increased expression of this specific miRNA in the AD brain leads to down-regulation of autophagy effectors, which is then responsible for reduced clearance of Aβ by microglia. In Aim 1, we will determine the mechanism underlying elevated expression of the miR. In Aim 2, we will investigate the functional consequences of reducing this miR in the brain of AD mouse and the mechanism by which the microRNA is upregulated in AD brain. We will determine the behavior of microglia isolated from treated mice. These experiments will be performed using the AD mouse model 5XFAD and human samples from AD and non-AD patients. Our proposal will characterize a novel drug target and mode of delivery for AD.