Direct Evidence for Self-Propagation Different Amyloid-β Fibril Conformations

Background: Amyloid fibrils formed by amyloid-beta (A beta) peptides are associated with Alzheimer's disease and can occur in a range of distinct morphologies that are not uniquely determined by the A beta sequence. Whether distinct conformations of A beta fibrils can be stably propagated over multiple cycles of seeding and fibril growth has not been established experimentally. Objective: The ability of the 40-residue peptide A beta(1-40) to assemble into fibrils with the conformation of the mutant A beta(1-40) peptide containing the 'Osaka' mutation E22 Delta, was investigated. Methods: Fibril formation of highly pure, recombinant A beta(1-40) in the presence of distinct, preformed seeds in vitro was recorded with thioflavin T fluorescence, and distinct fibrillar structures were identified and distinguished by fluorescence spectroscopy and electron microscopy. Results: We propagated the specific quaternary structure of A beta(1-40) E22 Delta fibrils with wild-type A beta(1-40) over up to seven cycles of seeding and fibril elongation. As a result of a 107-fold dilution of the initially present A beta(1-40) E22 Delta seeds, the vast majority of fibrils formed after the seventh propagation cycle with A beta(1-40) did not contain a single molecule of A beta(1-40) E22 Delta, but still retained the conformation of the initial A beta(1-40) E22 Delta seeds. Increased critical concentrations of A beta(1-40) fibrils formed in the presence of A beta(1-40) E22 Delta nuclei suggest that these fibrils are less stable than homologously seeded A beta(1-40) fibrils, consistent with a kinetically controlled mechanism of fibril formation. Conclusion:The propagation of a distinct A beta fibril conformation over multiple cycles of seeded fibril growth demonstrates the basic ability of the A beta peptide to form amyloid strains that in turn may cause phenotypes in Alzheimer's disease. (C) 2014 S. Karger AG, Basel