Tauopathy strains differentially replicate in vitro in the presence of mutant tau monomer

Tauopathies are a group of neurodegenerative diseases caused by misfolding of the protein tau into a β-sheet rich conformation. By inducing misfolding of additional tau monomers, these pathogenic fibrils replicate and spread progressive disease throughout the brain. While frontotemporal lobar degenerative diseases (FTLDs) - including argyrophilic grain disease, corticobasal degeneration, globular glial tauopathy, and progressive supranuclear palsy - are caused by this same underlying molecular process, each disease is defined by a unique clinical and neuropathological presentation. This phenomenon is explained by the strain hypothesis, which proposes that the conformation tau misfolds into determines which disease a patient will develop. Indeed, robust structural and biological data indicate that tau misfolds into conformational arrangements specific to each disease. While these findings are highly impactful for understanding similarities and differences between tauopathies, they have yet to be harnessed to develop a definitive ante-mortem diagnostic. Working toward the goal of disease-specific diagnostics, we created a panel of tau bioreporter cell lines expressing a fragment of human tau fused to yellow fluorescent protein (YFP). Using point mutations designed to interfere with tau misfolding into specific conformations, we quantified YFP-positive puncta after incubating cells with tau fibrils from FTLD patient samples to establish a strain-specific profile for each tauopathy. Not only can we use this approach to differentiate between human tau strains, but we also show that the tau strain found in a commonly used mouse model exhibits properties that significantly differ from those seen in human patients.