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.