Alzheimer disease (AD) and related tauopathies are major diagnostic, therapeutic, and clinical challenges. Our previous work suggest that different tauopathies are based on unique tau aggregate conformations, or ?strains,? and that strain identity predicts specific disease progression patterns in animal models. We hypothesize that distinct, self-propagating tau strains can move between cells of the brain to propagate pathology in humans. Recent publications from our group indicate that tau monomer in fact encodes strains. However this has not been rigorously tested across tauopathies. We will test this idea first by determining whether tau monomer encodes the same sets of strains encoded by larger assemblies in human brain (Aim 1). Next we will use multiplex biosensors to classify monomer from human tauopathies, and determine whether monomer can classify individuals in correlation with neuropathology with the same fidelity as larger assemblies. We will also test the fidelity of strain propagation in human neurons vs. HEK293 cells in comparison those strains isolated directly from human brain (Aim 2). Finally, we use structural biology approaches to determine the conformations of seed-competent monomer. In particular, we will determine whether local structures in tau predict its subsequent assembly into fibrils. This will be based on crosslinking mass spectrometry, molecular modeling, cryoEM, and microcrystallography. We predict that tau monomer will encode strain composition across tauopathies. If we are successful, we anticipate ultimately that it will be possible to classify tauopathies based on the conformation with tau monomer. This could have important implications for accurate diagnosis and personalized therapy.
Alzheimer disease and related tauopathies are major diagnostic, therapeutic, and clinical challenges but new data suggests that conformational ensembles of the tau monomer might hold the key to understanding the basis of clinical diversity. Our study seeks to determine the structure of seed- competent tau monomer (which self-assembles and serves as a template for fibril growth), to test the relationship of tau monomer conformation to the conformation of larger assemblies. This will greatly advance our ability to classify diseases, potentially using tau monomer recovered from biofluids, and to develop more personalized therapies.
