Tauopathies, including Alzheimer’s disease, are a group of neurodegenerative diseases characterized by the aggregation of pathologically modified tau proteins in human brains. Although several hypotheses have been proposed, the pathology underlining tau-mediated neurodegeneration needs further understanding. To address this gap in knowledge, our research group devised a proteomics approach in order to identify novel proteome changes associated with tau-mediated neurodegeneration using a tauopathy mouse model. Results showed depletion of the synaptic protein amphiphysin-1 (AMPH1) in brains regions affected by pathological tau species. The physiological implications of AMPH1 protein level reduction rely on the central role it plays in synaptic vesicle endocytosis, an essential process for neuronal function. Altogether, these observations suggest a link between AMPH1 and tau-mediated neurodegeneration. The paradigms explored in this study tested this idea by characterizing the tau-dependent AMPH1 depletion, age-dependently and mechanistically.