Progressive synapse loss is arguably one of the most important characteristics of neurodegenerative diseases - irrespective of the underlying proteinopathy: it is highly correlated with the occurrence of disease symptoms such as cognitive or motor decline and, thus, is a major structural cause of disease. However, innovative tools to study pathways that drive synapse loss in neurodegeneration have been missing. Here, we propose to develop and validate a tool in mouse models with Tau pathology, with which we can induce or halt synapse loss in the murine hippocampus. We will use this novel mouse model system to study multi-cellular interactions between neurons and glia cells during synapse loss by interrogating multi-cellular transcriptomic changes at the singlecell level and investigating cell-cell communication at nanoscale resolution by tissue expansion microscopy. Using these innovative techniques, we want to better define multicellular pathways that are involved in synapse loss for future modulation of these pathways in patients.