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Parthasarathy S, Inoue M, Xiao Y, Matsumura Y, Nabeshima Y, Hoshi M, Ishii Y. Structural Insight into an Alzheimer's Brain-Derived Spherical Assembly of Amyloid β by Solid-State NMR. J Am Chem Soc. 2015 May 27;137(20):6480-3. Epub 2015 May 18 PubMed.
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NIDDK, NIH
This structural model for Aβ42 fibrils is surprisingly different from existing models for Aβ40 fibrils. The peptide backbone conformation is different, and the contacts between amino acid side chains are different. For example, most Aβ40 fibrils have contacts between side chains of Phe19 and Leu34. Some Aβ40 fibrils have contacts between side chains of Asp23 and Lys28. These contacts are not present in the Aβ42 fibrils examined by Ishii and coworkers. As they suggest, these pronounced differences in backbone conformation and side chain contacts may explain the lack of efficient cross-seeding between Aβ42 fibrils and Aβ40 fibrils.
In general, Aβ fibrils are polymorphic, meaning that the same peptides can form multiple types of fibrils with different internal molecular structures. It is still possible that certain Aβ42 fibril structures have structures that are more similar to those of Aβ40 fibrils, and that certain Aβ42 fibrils are indeed capable of seeding the growth of Aβ40 fibrils. In future studies, it will be important to characterize structures of Aβ42 fibrils that develop in human brain tissue (as opposed to fibrils grown in vitro). In 2013, my group published a structural model for Aβ40 fibrils from brain tissue (Lu et al., 2013), but so far this has not been done for Aβ42 fibrils. It will be interesting to see how different the brain-derived fibril structures are.
References:
Lu JX, Qiang W, Yau WM, Schwieters CD, Meredith SC, Tycko R. Molecular Structure of β-Amyloid Fibrils in Alzheimer's Disease Brain Tissue. Cell. 2013 Sep 12;154(6):1257-68. PubMed.
UCLA Neuropsychiatric Institute
The authors describe the results of a solid-state NMR study on amylospheroid (ASPD), a toxic Aβ1-42 oligomer. They demonstrate the similarity of the synthetic ASPD to native ASPD and go on to suggest that the secondary structure of this particle is largely parallel β sheet. They further suggest this method may be suitable to study other toxic amyloid oligomers. Understanding the structure of toxic Aβ oligomers is a hot topic in the field, as we all hope to understand pathogenicity through structural knowledge. This has been difficult to date due to the technical problems of Aβ oligomer assembly and structural determination of polymorphic complexes. Repetition of this work by others will be critical to defining its usefulness. The suggestion that β sheet is a prominent structure within the particle is not unexpected, but has profound implications for toxicity. The tendency of β sheet structures to be pore-forming peptides is well established, and these data lend further weight to the notion that pore formation may play a role in amyloid toxicity. A major obstacle to further work is the fact that the relevant toxic structures may form in a membrane environment that may differ substantially from the aqueous phase. Still, this research establishes a method for structure determination that is quite powerful and could lead to significant advances. Since so many toxic oligomer species have been described, caution is warranted before we crown any particular one as the "pathogenic species."
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