CBD and PSP cell-passaged Tau Seeds Generate Heterogeneous Fibrils with A sub-population Adopting Disease Folds

Abstract

AbstractThe recent discovery by cryo-electron microscopy that the neuropatho-logical hallmarks of different tauopathies, including Alzheimer’s disease, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), are caused by unique misfolded conformations of the protein tau is among the most profound developments in neurodegenerative disease research. To capitalize on these discoveries for therapeutic development, one must achievein vitroreplication of tau fibrils that adopt the rep-resentative tauopathy disease folds - a grand challenge. To understand whether the commonly used, but imperfect, fragment of the tau pro-tein, K18, is capable of inducing specific protein folds, fibril seeds derived from CBD- and PSP-infected biosensor cells expressing K18, were used to achieve cell-free assembly of naïve, recombinant 4R tau into fibrils without the addition of any cofactors. Using Double Electron Electron Resonance (DEER) spectroscopy, we discovered that cell-passaged patho-logical seeds generate heterogeneous fibrils that are distinct between the CBD and PSP lysate-seeded fibrils, and are also unique from heparin-induced tau fibril populations. Moreover, the lysate-seeded fibrils contain a characteristic sub-population that resembles either the CBD or PSP disease fold, corresponding with the respective starting patient sam-ple. These findings indicate that CBD and PSP patient-derived fibrils retain strain properties after passaging through K18 reporter cells.