Synaptic dysfunction and cognitive decline in Huntington's disease (HD) involve hyperactive A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10). To identify the molecular mechanisms through which ADAM10 is associated with synaptic dysfunction in HD, we performed an immunoaffinity purification-mass spectrometry (IP-MS) study of endogenous ADAM10 in the brains of wild-type and HD mice. In the normal brain, proteins implicated in synapse organization, synaptic plasticity, and vesicle and organelles trafficking interact with ADAM10, suggesting that it may act as a hub protein at the excitatory synapse. Importantly, the ADAM10 interactome is enriched in presynaptic proteins and ADAM10 coimmunoprecipitates with piccolo (PCLO), a key player in the recycling and maintenance of synaptic vesicles (SVs). In contrast, reduced ADAM10/PCLO immunoprecipitation occurs in the HD brain, with decreased density of SVs in the reserve and docked pool at the HD presynaptic terminal. Conditional heterozygous deletion of ADAM10 in the forebrain of HD mice reduces active ADAM10 to wild-type level, and normalizes ADAM10/PCLO complex formation and SVs density and distribution. The results indicate that presynaptic ADAM10 and PCLO are a relevant component of HD pathogenesis.