SUMMARY AND CONCLUSIONS
This is the second paper of a series on the concentric β-barrel hypothesis for non-fibril amyloid assemblies; the first was on Synucleins, especially α-synuclein associated with Parkinson’s Disease42. These papers are follow-ups to and expansion of our earlier publications on concentric β-barrel models of Aβ42 oligomers, APFs, and ion channels22,23, utilizing recent experimental results and image averaging. Some may consider Aβ42 APFs of secondary interest because they are not toxic and do not form transmembrane channels39. Nonetheless, we have chosen to emphasize them because they provide the best pictorial evidence we have for concentric structural architectures. They also provide clues to the structure of smaller oligomers, which are thought to be important in Alzheimer’s disease and may be precursors to transmembrane channels.
Hypothetical models and concepts are vital for research because they may suggest experiments that otherwise would not be performed or funded. Alternative models such as those described in the Supplement are useful because they make different predictions that can be tested. For example, the same residue of adjacent monomers interacts at axes of 2-fold perpendicular symmetry, but the predicted interactions differ among models. Introduction of a cysteine residue at these positions could create disulfide-linked dimers that stabilize some assemblies while preventing formation of others. Doing so could reduce the polymorphism, reduce disorder that complicates structural studies of amyloids, and help identify which models are better. Likewise, models of oligomers can be used to identify possible target segments to which binding of antibodies or drugs could preclude farther growth of the assembly. Thus, having a basic understanding of how amyloids develop and morph among many experimentally observed configurations may provide new insights for development of molecular preventions, treatments, and possibly cures of the devastating diseases associated with amyloid misfolding.
Authors’ contributions:
Most of the theory and graphics were developed by HRG, who wrote most of the text. SRD developed the β-barrel software and co-created the 3D versions of the models, and provided valuable suggestions for the theory, figures, and editing of the manuscript. RK performed the EM studies of the annular protofibrils and provided the EM images.
The authors have no competing interests.
Original EM images will be supplied by HRG at hrguy46@yahoo.com upon request.
This work was supported in part by the Intramural Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.