Abstract
Tau fibrils are pathological aggregates that can transfer between neurons and then recruit soluble Tau monomers by template-assisted conversion. The propagation of different fibril polymorphs is thought to be a contributing factor to phenotypic diversity in Alzheimer disease and other Tauopathies. We found that a homogeneous population of Tau fibrils composed of the truncated version K18 (residues 244–372) gradually converted to a new set of fibril conformers when subjected to multiple cycles of seeding and growth. Using double electron-electron resonance (DEER) spectroscopy, we observed that the distances between spin labels at positions 311 and 328 in the fibril core progressively decreased. The findings were corroborated by changes in turbidity, morphology, and protease sensitivity. Fibrils that were initially formed under stirring conditions exhibited an increased fragility compared with fibrils formed quiescently after multiple cycles of seeding. The quiescently formed fibrils were marked by accelerated growth. The difference in fragility and growth between the different conformers explains how the change in incubation condition could lead to the amplification of a minor subpopulation of fibrils. Under quiescent conditions where fibril breakage is minimal, faster growing fibrils have a selective advantage. The findings are of general importance as they suggest that changes in selective pressures during fibril propagation in the human brain could result in the emergence of new fibril conformers with varied clinicopathological consequences.
Highlights
To gain insights into the core of Tau fibrils beyond strandregistry, we recently introduced pairs of spin labels into the third repeat of K18 and K19 and measured the distances between them [47] using a technique called double electronelectron resonance (DEER) spectroscopy [48, 49]
Tau Fibril Populations Evolve during Consecutive Cycles of Seeding and Growth—The ability to form distinct fibril conformers from proteins with identical sequence and to perpetuate these conformers by template-assisted conversion is a unique property of amyloids [57]
Since the conformers compete for the same pool of Tau monomers we wanted to explore the relative stabilities of these species
Summary
3R, 3-repeat; EPR, electron paramagnetic resonance; DEER, double electron-electron resonance; 4R, 4-repeat; PK, proteinase K. To gain insights into the core of Tau fibrils beyond strandregistry, we recently introduced pairs of spin labels into the third repeat of K18 and K19 and measured the distances between them [47] using a technique called double electronelectron resonance (DEER) spectroscopy [48, 49]. As these distances are intramolecular in nature, they provide information on the structural relationships within different parts of the same protein. The findings have important implications for the propagation of Tau fibrils in the human brain
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