Project Summary/Abstract Recently, significant progress in understanding Tau aggregation and how Tau aggregates lead to neurodegeneration has been made by the description of the atomic structures of Tau filaments isolated from brain. The atomic models of Tau in Alzheimer disease (AD), Pick disease, Corticobasal degeneration, and Chronic Traumatic Encephalopathy were determined by cryo- electron microscopy (cryo-EM) through an ongoing collaborative effort between our laboratory at Indiana University and the MRC Laboratory of Molecular Biology. Additional Tau structures are also currently being identified in a collaborative effort between Indiana University and Purdue University. The studies proposed in this MPI application are a logical continuation of this groundbreaking work. The main goals of this project are to elucidate the structural basis and pathological mechanisms implicated in Gerstmann-Sträussler-Sheinker (GSS, F198S) disease and Prion protein cerebral amyloid angiopathy (PrP-CAA, Q160X), in which Tau deposits are composed by 3R+4R Tau, as in AD. We will determine the atomic structure of Tau through cryo- EM, the role of post-translational modifications of Tau filaments in relation to structure and perform in vitro and in vivo analysis of Tau seeding and propagation. The investigation of what drives the specificity of Tau conformers in Tau pathology is an essential step toward the design of novel diagnostic and therapeutic molecules.

Project Narrative Although most studies in Alzheimer disease (AD) so far have focused on amyloid β, interest in Tau is growing because of the discovery of the central role of Tau in neurodegeneration and the difficulties associated with the targeting of amyloid β to develop mechanism-based treatments for AD. The main goals of this project are to elucidate the structural basis and pathological mechanisms implicated in Gerstmann-Sträussler-Sheinker (GSS, F198S) disease and Prion protein cerebral amyloid angiopathy (PrP-CAA, Q160X), in which Tau deposits are composed by 3R+4R Tau, as in AD.