PROJECT SUMMARY/ABSTRACT The recent wave of cryo-electron microscopy (cryo-EM) studies on amyloid fibrils has highlighted the complexity of protein deposition amongst patients of amyloid diseases. A convincing example is found in tau, a microtubule binding protein whose pathological aggregation causes tauopathies. Each of these tauopathies seems to be associated with a particular structural assembly, suggesting causality. Similar to tauopathies, other amyloid diseases manifest differential prognosis, onset, and symptomatology. This is the case of TDP-43, α-synuclein, β-amyloid, or transthyretin (TTR), to name a few. We hypothesize that these phenotypical differences are driven by the formation of various structural assemblies, similar to what is found in tau. As a consequence, the detection of these disease-specific assemblies in a timely manner could ensure proper diagnosis and treatment. We aim to map the structural spectrum of amyloid fibrils in an amyloid disease model using cryo-EM and a co- culture system to be developed in our laboratory. Using the obtained structural information, our laboratory will design structure-specific peptides for the detection and inhibition of amyloid fibrils in cells, mice, and patient- derived samples. If successful, our study will serve as a launching platform for the development of personalized structure-based diagnostics and therapeutics for amyloid diseases.