title: Fracture and Growth Are Competing Forces Determining the Fate of Conformers in Tau Fibril Populations.
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.
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208.
authors.forename: Virginia
authors.initials: V
authors.lastname: Meyer
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Holden
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208.
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Weismiller
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208.
authors.forename: Gareth R
authors.initials: GR
authors.lastname: Eaton
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208.
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Eaton
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208 martin.margittai@du.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Margittai
mesh_terms: D000595:Amino Acid Sequence; D004578:Electron Spin Resonance Spectroscopy; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008854:Microscopy, Electron; D009154:Mutation; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure
chemical_list: D016875:tau Proteins
keywords: Alzheimer disease; Tau protein (Tau); aggregation; amyloid; electron paramagnetic resonance (EPR); fibril; prion