FIGURE 12.

Schematic summary of oligomer-fibril interconversion mechanisms. An amyloid protein (e.g. Aβ42) is depicted as a U-turn of two β-strands. The green β-strand is N-terminal to the yellow β-strand. Oligomers are known to take many forms, two of which are represented here: β-cylindrin (77) (Oligomer 1, represented as a cylinder) and cross-β oligomers (Oligomer 2, represented as a stack of U-turns) (Stroud et al. (18) and this work). Fibril seeds have an amyloid spine made of a pair of β-sheets, represented as laminae upon which β-strands are superimposed). Unlike oligomers, which are limited in size, fibrils have either one or two growing ends onto which monomers may add indefinitely. A, in conversion by homogeneous nucleation, oligomers (shown here as a cylinder), must first dissociate before nucleating to form fibril seeds. B, in conversion by secondary nucleation, oligomers with fibril-like structure (as described in the present work) may add new monomers that form a fibril repeat different from the oligomer repeat. In the context of amyloid, such differences in repeats are known as polymorphisms. The example of polymorphism conversion by packing polymorphism is shown here. C, oligomers may convert to fibrils by nucleated conformational conversion (35). Two types of nucleated conformational conversion have been proposed: barrel unrolling and strand rotation. In conversion by barrel unrolling, an amyloid oligomer β-barrel (i.e. β-cylindrin) breaks open by dissolution of β-hydrogen bonding between one pair of β-strands to produce a linear β-sheet (77). To form a fibril seed, two such linear sheets must interact through lateral association. Strand rotation conversion, described in the present work and elsewhere (74, 75), entails the rotation of β-strands by ∼90° around their long axes. This rotation turns the β-sheets of the oligomer (running horizontally in the bottom panel) into fibril β-sheets (running vertically).