The work proposed in this application stems from dramatic advances in our understanding of reasons that nerve cells die in Alzheimer’s disease. This work derives from new insights into how our bodies respond to stress. We have discovered a group of proteins, termed RNA-binding proteins (RBPs), that bind directly to tau protein (one of the major proteins that accumulates in the brains of patients with Alzheimer’s disease). Binding of these RBPs causes tau to form small clumps, termed oligomers, which are very harmful. In parallel studies we have found that reducing one of these RBPs prevents disease and prolongs survival in an animal model of Alzheimer’s disease. However, there actually are multiple RBPs that associate with tau in disease, and we don’t know which RBP is the best target for therapeutic development. In this proposal, we will test each of the RBPs that we find associated with tau pathology and determine which is the best target for future drug development. This project also will address another key part of testing the utility of our approach for therapeutic development. Until now, our studies all have been done in mouse models. Recently, scientists have figured out how to grow human nerve cells from patients with Alzheimer’s disease in culture in a way where the nerve cells develop some of the aspects of Alzheimer’s disease. In this project, we will import this technology and test whether reducing RBPs in human nerve cells (similar to those in our brain) also protects against the changes seen in the brains of patients with Alzheimer’s disease.