An emerging pathophysiological mechanism influencing Alzheimer’s disease (AD) is neuroinflammation, characterized by elevated levels of pro-inflammatory molecules, reactive astrocytes and microglia that span across the course of the disease, potentially influencing disease progression. The role of astrocytes and their contribution to AD development and progression has remained mostly unexplored. In the proposed studies, we aim to determine the influence of astrocytic-dependent inflammation on progressing tau pathology in the presence of plaque burden. Additionally, we aim to identify a mechanism by which astrocytes expressing apolipoprotein E4 display neurotoxicity. These studies will clarify the therapeutic potential of reactive astrocytes and potentially provide new therapeutic targets.