PROJECT SUMMARY/ABSTRACT The cell-to-cell spread of pathogenic tau between neurons is a devastating hallmark of Alzheimer’s disease (AD) and other dementias. Recent evidence indicates that the neuronal receptor low-density lipoprotein receptor- related protein 1 (LRP1) is the critical receptor required for endocytosis of pathogenic tau, suggesting the blocking of LRP1-tau interactions as a therapeutic route. However, to achieve this requires comprehensive atomic-level characterization of LRP1-tau engagement, as well as the identification of potent molecular inhibitors and characterization of their mechanism of action. Work in the supplement, in response to NOT-AG-21-018 entitled “Alzheimer’s-Focused Administrative Supplements for NIH Grants that are Not Focused on Alzheimer’s Disease” directly addresses key gaps in treatment of Alzheimer’s Disease in the context of blocking pathogenic- tau. We demonstrate that LRP1 directly engages tau, which we will block with our recently discovered Rift Valley Fever Virus glycoprotein N (RVFV Gn) that also directly binds LRP1. Using protein engineering, we will build multivalent tau inhibitors, test their efficacy in tau binding and spreading, and evaluate the impact in a mouse model. We will test the significance of Lrp1 in mouse models of AD. Altogether, this work will provide the framework needed to develop potential viral glycoprotein-based therapies to prevent the spread of pathogenic tau, addressing an urgent unmet need.