Mapping FTD Tau Amyloid Interactions using a De Novo Designed Soluble Protein Amyloids are hallmarks of Alzheimer’s Disease (AD) and Alzheimer’s Disease-Related Dementias (ADRD). In these diseases, amyloidogenic proteins (e.g., tau) misfold and coalesce to form insoluble deposits, which appear as microscopic lesions in patient brain samples. With cryo-EM advancement, the number of solved high-resolution amyloid structures is on the rise. Each amyloidogenic protein can adopt a number of different three-dimensional amyloid structures, each with distinct molecular repeating structures, which is defined as conformational strains. Interestingly, distinct tau conformational strains are correlated to different clinicopathological presentations of AD and ADRD—strains are homogeneous within a disease type but vary between diseases. There is currently a lack of methods to artificially recreate the AD and ADRD patient-observed conformational strains in the lab, which is a major setback for the study of biologically relevant species and a barrier to understanding the pathological effects of amyloids. This highlights the need for new methods to present the AD and ADRD patient-observed amyloid epitopes. Additionally, amyloids are inherently insoluble, making it difficult to use traditional drug screening methods to identify potential treatments, highlighting the need to generate large quantities of soluble forms for drug development efforts. This proposal aims to create innovative computational tools to rebuild tau amyloid epitopes observed in frontotemporal dementia (FTD) tauopathy patients and validate in situ. The designed proteins will then be utilized to investigate how the tau amyloid epitopes interact with its biochemical microenvironment to elucidate their causal role in tau-mediated pathogenesis and to begin development of effective therapies for FTD tauopathy. The protein design canvas is a β-solenoid supersecondary structural motif which shares characteristics of supramolecular assembly of amyloids such as extensive parallel β-sheet with 4.8 Å spacing. The design focus is to patch FTD patient observed tau amyloid epitope onto a β-solenoid with capping moieties for solubility. I will validate the designed β-solenoid with X-ray crystallography and begin to probe tau amyloid epitope interaction with proteins and metabolites to understand how tau amyloids contribute to pathological events. The ultimate goal is to use these stable tau amyloid epitopes to produce monoclonal antibodies and perform high-throughput small molecule drug screening to identify therapeutics that target conformational strains of FTD tau amyloids.