Multiple assembly pathways underlie amyloid-beta fibril polymorphisms.
The amyloid beta-protein transiently forms low and high molecular mass oligomers and protofibrils in vitro, and after longer incubation times assembles into polymorphic mature fibrils. The precursor-to-product relationship of these species remains to be understood. Protofibrils are up to approximately 600 nm in length and have mass-per-lengths of 19(+/-2) kDa/nm measured by scanning transmission electron microscopy. Two predominant mature fibril types, several microns in length and with mass-per-lengths of 18(+/-3) and 27(+/-3) kDa/nm, are identified after longer incubation times. The difference of approximately 9 kDa/nm between the two fibril types indicates a bona fide elementary protofilament subunit of this mass-per-length. Fibrils in the 18(+/-3) kDa/nm group often exhibited distinct coiling with axial cross-over spacings of approximately 25 nm. Although strikingly different in morphology, the mass-per-length (MPL) of these coiled fibrils is equivalent to that measured for protofibrils. They could therefore arise from a conformational change in the protofibril concurrent with coiling and rapid elongation. Alternatively, we cannot rule out an assembly pathway not directly related to protofibrils. In contrast, the 27(+/-3) kDa/nm fibrils correspond to a MPL of approximately 1.5 x the protofibril and thus can neither arise from a simple conformational transition nor from lateral association of 19 kDa/nm protofibril precursors. Twisted ribbons with axial periodicities ranging from approximately 80 nm to 130 nm were prominent in the 27(+/-3) kDa/nm group as well as more tightly coiled fibrils. Individual fibril ribbons had elongation rates of 20(+/-12) nm/min when imaged by time-lapse atomic force microscopy. Protofibrils exhibited growth rates approximately 15 x slower at 1.3(+/-0.5) nm/min. The data support a model where concurrent multiple assembly pathways give rise to the various polymorphic fibril types.
Goldsbury
Claire
C
M.E. Müller-Institute for Structural Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
Frey
Peter
P
Olivieri
Vesna
V
Aebi
Ueli
U
Müller
Shirley A
SA
D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001572:Benzofurans / Q000737:chemistry; D006801:Humans; D018625:Microscopy, Atomic Force; D008854:Microscopy, Electron; D008970:Molecular Weight; D010446:Peptide Fragments / Q000737:chemistry*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D001572:Benzofurans; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C474023:iAbeta5 peptide