Cofactor-Free Serial Amplification of Tau Filaments from Alzheimer’s Disease and Other Tauopathies Depends on the Conformational State of Tau Monomers

Tau filaments are a defining characteristic of Alzheimer's disease (AD) and numerous other neurodegenerative disorders. The deposition of Tau protein into aggregates involves templated recruitment of Tau monomers onto the filament ends via their microtubule-binding repeats. This structural conversion is central to the propagation of Tau pathology, yet its molecular mechanisms are still poorly understood. Specifically, it is unclear whether cofactors are required for templated growth. To gain insights into this process, we probed the serial amplification of pathological Tau filaments from AD, Pick's disease (PiD), and progressive supranuclear palsy (PSP). These filaments are made from different compositions of three- and four-repeat (3R and 4R) Tau. We observe that AD Tau filaments recruit full-length 3R and 4R Tau in the absence of cofactors at low salt concentration but not at physiological salt concentration and that these filaments can be independently amplified over multiple generations. PiD Tau and PSP Tau filaments can be similarly amplified. The generated filaments retain the cross-seeding properties of the pathological seeds; PSP filaments recruit only 4R Tau, PiD filaments recruit only 3R Tau, and AD filaments recruit both. Regardless of the structural fidelity of the amplification process, we show that the Tau monomer ensemble serves as an entry point for templated growth and that the conformational state of this ensemble (expanded versus compact) determines whether propagation occurs.