Multiple assembly pathways underlie amyloid-β 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 similar to 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 similar to 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 similar to 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 similar to 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 similar to 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 similar to 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. (c) 2005 Elsevier Ltd. All rights reserved.