Tau protein forms highly ordered aggregates that underlie diverse neurodegenerative diseases termed “tauopathies.” Each tauopathy is associated with unique tau assembly structures, but it is unknown how these distinct structures initially form. Our work suggests that RNA is a trigger for these conformational changes in tau. RNA plays different roles in cells. One is to encode proteins, but many other forms of RNA regulate gene expression and contribute to the structures of intracellular molecular machines. We have found that a class of small RNAs (less than 200 nucleotides, and not likely to encode proteins) is particularly potent at inducing tau to form structures that could play a role in disease. We also have found that the pathological tau assemblies of Alzheimer’s disease are stabilized by binding RNA. This leads us to speculate that RNA plays a critical role in the initiation of pathology in Alzheimer’s disease. In this proposal, we will determine what specific forms of RNA bind and convert tau to a pathological state, using cell models and tau extracted from human brain. We will test the idea that unique conformations of tau are initiated and sustained by specific RNA molecules.