Amyloid fibril polymorphism

In this chapter, we first describe amyloid fibril polymorphism as seen by EM. We then show how SFM was used to depict intermediate stages of amyloid fibril assembly. Finally, we discuss the putative mechanism that might explain the cytotoxicity induced by these assembly intermediates. 

The most detailed accounts of amyloid fibril polymorphism have come from EM studies of four different proteins or peptides, namely amyloid-/) (A/ l 4o or A/i v). transthyretin, calcitonin, and human amylin. The fibrils... 

Fig. 3. A generalized model of amyloid fibril polymorphism based on the formation of straight or coiled fibrils composed of several 4- to 5-nm-wide protofibril subunits. Notice that the flat ribbons containing several protofibril strands may twist (Fig. 2F and G) and may ultimately form tubes (Bauer et al, 1995).

These three examples emphasize the idea that a complete description of amyloid fibril polymorphisms will only be achieved when 3D structures at atomic detail become available (Luhrs et al., 2005). Last but not least, since the various morphologies observed for amyloid fibrils are defining the end point of the assembly process, an essential need is to properly define the early stages of fibril formation, namely the oligomeric states of the peptide or protein in solution prior to assembly into fibrils. 

Now that we have defined the starting point and the final products of the assembly process, the next step is to investigate the origin of amyloid fibril polymorphism through a detailed study of the assembly pathways... 

Amylin fibrils growing on mica were rather straight and exhibited various heights. They were compatible with the protofibril hypothesis of amyloid fibril polymorphism (Fig. 3), but no multistranded cables were present (Goldsbury et al, 1999). In contrast, coiled fibrils were often observed by SFM for fibrils assembled in solution prior to being adsorbed to mica (Jansen et al, 2005 Kad et al, 2003 Relini et al, 2004). In the case of... 

From the Polymorphism of Amyloid Fibrils to Their Assembly Mechanism and Cytotoxicity... 

FROM THE POLYMORPHISM OF AMYLOID FIBRILS TO THEIR ASSEMBLY MECHANISM AND CYTOTOXICITY... 

Unfortunately, the description of amyloid fibrils given above is simplistic since in vitro self-assembly of amyloid peptides and proteins yields polymorphic structures, as has been commonly observed in the past for other protein assemblies such as actin filaments (Millonig et al, 1988) and intermediate filaments (Herrmann and Aebi, 1999). On the one hand, assembly polymorphism complicates the characterization of fibril structure. On the other hand, it offers some insight into fibril formation. For this reason a more rational understanding of amyloid fibril formation at the molecular level is a key issue in the field of amyloidosis. 

Fig. 2. Electron micrographs highlighting the polymorphism of amyloid fibrils. (A) A single human calcitonin protofibril with a diameter of 4 nm (adapted from Bauer et al., 1995). (B) Different morphologies present in a transthyretin fibril preparation. Black arrowheads show oligomers of different sizes, the black arrow points to a 9- to 10-nm-wide fibril, and the white arrowhead marks an 4-nm-wide fibril (adapted from Cardoso et al., 2002). (C-F) Human amylin fibril ribbons (adapted from Goldsbury et al., 1997). (C) A single 5-nm-wide protofibril. (D-F) Ribbons containing two (D), three (E), or five (F) 5-nm-wide protofibrils. (G) A twisted ribbon made of four 5-nm-wide protofibril subunits of Api-40 (adapted from Goldsbury et al., 2000b). Scale bar, 50 nm (A-G).

In the case of human amylin and Afi our understanding of the diversity in amyloid fibril architecture is the result of a recursive process, since the early morphological observations were followed by assessment of the assembly pathway which in turn yielded a better understanding of fibril polymorphism. However, this structural knowledge is secondary compared to the discovery of small oligomers, globular oligomers, and early protofibrils that appear to be extremely cytotoxic (Hartley etal., 1999 Lambert et al, 1998 Walsh et al, 1999). 

Goldsbury, C., Frey, P., Olivieri, V., Aebi, U., and Muller, S. A. (2005). Multiple assembly pathways underlie amyloid-beta fibril polymorphisms./. Mol. Biol. 352, 282-298. 

Petkova, A. T., Leapman, R. D., Guo, Z., Yau, W. M., Mattson, M. P., and Tycko, R. (2005). Self-propagating, molecular-level polymorphism in Alzheimer s beta-amyloid fibrils. 

Lessons from Studying Conformational Polymorphism in Amyloid Fibrils. 153... 

The notion that prion strains are encoded by different conformations of the same protein is supported by a wealth of data showing structural polymorphisms (or strains ) in amyloid fibrils formed by a number of unrelated proteins such as insulin [160], Alzheimer s A(3 peptide [161], and Sup35 [107, 108]. Importantly, the conformational traits defining individual polymorphic forms are often heritable upon seeding, with daughter fibrils adopting the conformation of parent seeds, even if the reaction is performed under conditions that would normally favor... 

Lee M, Baek I, Chang HJ, Yotm G, Na S (2014) The bond survival time variation of polymorphic amyloid fibrils in the mechanical insight Chtan Phys Lett 600 68-72... 

Petkova AT, Leapman RD, Guo Z, Yau W-M, Mattson MP, Tyeko R (2005) Self-propagating, molecular-level polymorphism in Alzheimer s B-amyloid fibrils. Scitmce 307(5707) 262-265... 

Chun et al. (2012] report on higher-order suprastructures obtained in the presence of dithiothreitol and heat treatment of /c-casein that transforms into amyloid fibrils with distinctive morphology attributable to mechanism-based fibrillar polymorphism. The hydrogel was demonstrated to be used for the controlled release of bioactive compound like retinoic acid, which led to temporal and spatial control over the neuronal differentiation. 

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