Neurodegenerative diseases such as Alzheimer’s appear to progress along brain networks. This idea is supported by experiments in cell and mouse models. We have proposed that pathological forms of the tau protein, which accumulates in Alzheimer’s brain as neurofibrillary tangles, move between brain cells to spread pathology. This involves formation and release of tau “seeds,” which are small assemblies that can serve as templates for their own replication in cells. Once they enter cells, it is unknown how tau aggregates can replicate. We used a system termed “proximity labeling” to identify cellular factors that interact with tau as it begins the amplification process. We identified valosin-containing protein (VCP/p97) as the main interactor. The gene coding for VCP was coincidentally identified as having mutations in a family of patients with dominantly inherited tauopathy, indicating that the VCP gene plays a causal role in disease. We have studied the VCP protein in detail using genetics and chemical inhibitors and learned that it regulates the replication of tau seeds (both up and down) immediately after they gain access to the cytoplasm. This indicates that VCP could be an excellent target to treat tau pathology. This proposal will expand our understanding of the molecular mechanisms that govern tau replication by identifying and characterizing which of the myriad VCP-interacting proteins allow it to dynamically regulate this process.