Many scientists believe that plaques made of amyloid peptide contribute to brain degeneration in people with Alzheimer’s disease. Moreover, fibrils of a 42-amino-acid fragment of this peptide are increasingly thought to be the main culprits in triggering plaque formation. But structural information about these fibrils has been hard to come by because they are heterogeneous.
Yoshitaka Ishii of the University of Illinois, Chicago, and coworkers now report generating a homogeneous Aβ-42 fibril in vitro and obtaining a model of its structure with solid-state nuclear magnetic resonance spectroscopy (Nat. Struct. Mol. Biol. 2015, DOI: 10.1038/nsmb.2991). The structure differs significantly from that of Aβ-40, Aβ-42’s shorter and more abundant sibling, which has also been implicated in Alzheimer’s.
Previously reported Aβ-40 fibrils are U-shaped with parallel β-sheets connected by a flexible loop. In contrast, this particular Aβ-42 fibril contains three connected β-sheets that adopt an S-shaped configuration.
Different interactions stabilize the Aβ-40 and Aβ-42 structures. The shorter peptide is held together by a salt bridge between lysine 28 and aspartic acid 23. Instead of that interaction, Aβ-42 forms a salt bridge between lysine 28 and alanine 42, a residue that doesn’t exist on the shorter peptide.
Previous structural studies by Robert Tycko at the National Institutes of Health and others have shown that amyloid-β fibrils having a given sequence can adopt multiple structures with subtle differences in configuration.
The new work is important, Tycko says, “because it demonstrates that conformational variations in amyloid-β fibrils can be dramatic.” In addition, the study suggests an explanation for why fibrils formed by Aβ-40 and Aβ-42 don’t “cross-seed,” or trigger one another to form fibrils, he says. “It remains to be seen whether the fibril structure described in this paper exists in human brain tissue,” he notes.
If the structure is found in the brain, drugs that have already been designed to optimally obstruct an arched β-motif in Aβ-40 may not work as well against Alzheimer’s, which might be caused by the more toxic Aβ-42 fibrils, Ishii and coworkers say.