The concept that astrocytes are actively involved in neural development, synapse formation and synaptic activity in the healthy brain has emerged during the last 15 years. In the diseased brain, such as in Alzheimer’s Disease (AD), we are just starting to probe whether dysregulated astrocytes significantly contribute to the pathology. Neurofibrillary tangles, made of hyperphosphorylated and aggregated Tau proteins, are an essential pathological neuronal feature of the AD brain. In the latter, progression of neuronal « Tau pathology », scored as the Braak stages, from entorhinal cortex to hippocampus and lastly neocortex, is associated with progression of clinical symptoms supporting a pivotal contribution of neuronal Tau pathology to cognitive deficits. Mechanisms for Tau pathology-induced cognitive deficits in AD remain poorly understood and most studies focus on neuron-autonomous dysregulations. Conversely, relationships between neuronal Tau pathology and astrocytes remain largely unknown. Our preliminary observations raise the hypothesis that neuronal Tau pathology induces astrocyte dysfunctions, possibly through a Tau transfer from neurons to astrocytes. In addition, we recently identified adenosine A2A receptors (A2ARs), G-protein-coupled receptors whose endogenous ligand is adenosine, as a mediator of these interactions between neuronal Tau pathology and astrocytes. In this context, our overall objective is to uncover the impact of neuronal Tau pathology towards astrocyte function and establish astroglial A2ARs as druggable regulators of the development of Tau pathology and associated memory deficits. We will explore this link using several mouse models combined with innovative viral methods and functional tools to specifically address several questions in FACS-sorted acstrocytes, regarding astrocyte morphology and activity, as well as modifications of astrocytic transcriptome and epigenome. Specifically, we will 1) evaluate whether and how neuronal Tau pathology affects astrocyte function including chromatin structure and gene profiles and 2) establish astrocyte A2A receptors as a druggable switch of Tau-induced astrocyte dysfunction. To achieve our goals, we have assembled the unique ADORASTrAU consortium which brings together three research teams sharing a common interest towards AD pathophysiology, with highly complementary, non-overlapping and non-interchangeable scientific expertise. Our project will provide original insights in the mechanisms by which Tau pathology impacts the function of astrocytes and determine to which extent adenosine A2A receptors could be a molecular switch of Tau-induced cognitive dysfunctions.