Colletier JP, Laganowsky A, Landau M, Zhao M, Soriaga AB, Goldschmidt L, Flot D, Cascio D, Sawaya MR, Eisenberg D.
Molecular basis for amyloid-beta polymorphism.
Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):16938-43.
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This paper from the Eisenberg group suggests several molecular structural models for fibrils formed by full-length β amyloid peptides, based on their crystal structures of segments of the full-length peptide that reveal the details of intermolecular interactions. Using solid-state NMR and electron microscopy measurements on full-length β amyloid fibrils, my group showed earlier that β amyloid can form multiple distinct fibril structures (i.e., multiple polymorphs), and we have published specific structural models for two polymorphs that give distinct NMR spectra and have distinct appearances in electron microscope images. These experiments were done on fibrils that were prepared in vitro from synthetic β amyloid peptide. Some of the models in the Eisenberg paper resemble our solid-state NMR-based models, while others are quite different. The total number of fibril structures that β amyloid can form has not been determined, but is at least five, based on results from Ron Wetzel's lab and my lab. The new fibril structures suggested in the Eisenberg paper are plausible, and may be identified in future studies of other full-length β amyloid fibril polymorphs.
We suggested in 2005 (Petkova et al., 2005) that β amyloid fibril polymorphism may have biomedical significance, with certain polymorphs effectively being more neurotoxic than others. We subsequently obtained evidence that fibrils in AD brain tissue have molecular structures that are different from our published structural models (Paravastu et al., 2009). We do not yet know whether there is a connection between variations in β amyloid fibril structure and the development of AD, but this remains a viable and interesting hypothesis that we are pursuing. The possibility exists that the structural models suggested in the Eisenberg paper do correspond to fibrils that occur in AD. Future experiments will provide more definitive information.
Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R.
Self-propagating, molecular-level polymorphism in Alzheimer's beta-amyloid fibrils.
Science. 2005 Jan 14;307(5707):262-5.
Paravastu AK, Qahwash I, Leapman RD, Meredith SC, Tycko R.
Seeded growth of beta-amyloid fibrils from Alzheimer's brain-derived fibrils produces a distinct fibril structure.
Proc Natl Acad Sci U S A. 2009 May 5;106(18):7443-8.
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