Implications for Alzheimer's disease of an atomic resolution structure of amyloid-β(1-42) fibrils.

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The article by Walti et al. (1) in PNAS is a milestone in biomedicine. It describes in atomic detail fibrils that form the plaques in diseased brains, first observed by Alois Alzheimer 110 y ago. These extracellular fibrils are now known to be composed of amyloid-β, a peptide of various lengths between 38 and 43 residues, proteolytically cleaved from the cell-surface membrane protein called amyloid precursor protein (APP). Amyloid-β(1–42) is more cytotoxic than its cousin, shorter by two residues, amyloid-β(1–40), for which structures have been known for several years (2). Because of its role in the etiology of Alzheimer’s disease, the structure of amyloid-β(1–42) has been eagerly awaited, and now two independent studies simultaneously describe identical, disease-relevant fibrils: the report by Walti et al. (1) is from the laboratories of Meier and Riek at Eidgenossiche Technische Hochschule Zurich and Bockmann at Lyon, and the other is from Griffin at the Massachusetts Institute of Technology and Linse at the University of Lund, Sweden (3). These structures are determined largely from distance constraints between pairs of isotopically labeled atoms measured by solid-state NMR. Computer-aided energy minimization of the amyloid-β(1–42) peptide chains yields a “bundle” of atomic models, each obeying the distance constraints. That is, the final structure is a constrained set of closely related models, rather than a single structure as yielded by a high-resolution X-ray determination or a direct image produced by cryo-EM. Although it is not possible to be certain that there is no other model that also fits the same NMR constraints, alternative models become increasingly improbable as the number of distance constraints grows. Confidence in the amyloid-β(1–42) structure is reinforced by the essentially identical results of the two independent studies. For the Walti et al. (1) structure, the rmsd of backbone atoms of the 10 lowest-energy atomic … [↵][1]1To whom correspondence should be addressed. Email: david{at}mbi.ucla.edu. [1]: #xref-corresp-1-1