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Alzheimer's disease

Structure of aggregates revealed

A technical feat achieved by two independent groups has enabled resolution of the molecular structure of a form of the amyloid-β protein that is thought to play a major part in Alzheimer's disease.

The aggregation of short amyloid-β (Aβ) proteins in brain tissue is widely thought to lead to Alzheimer's disease. Most Aβ aggregates take the form of filamentous assemblies called fibrils, which are typically 5–10 nanometres in diameter, and can be many micrometres long. The structural details of Aβ fibrils have proved tough to define, because the assemblies' insolubility and noncrystallinity prevent determination of their structures using standard methods. Now, two independent groups (Colvin et al.1, writing in the Journal of the American Chemical Society, and Wälti et al.2, writing in Proceedings of the National Academy of Sciences) report full molecular structures for fibrils formed by the version of Aβ comprised of 42 amino-acid residues (Aβ42), which is thought to be of primary importance in most cases of Alzheimer's disease3. Their findings have broad implications for our understanding of this disease and for the development of drugs and diagnostic imaging agents.

The new Aβ42 fibril structures are derived primarily from solid-state nuclear magnetic resonance (NMR) data. As the name suggests, solid-state NMR is aimed at samples that are not liquids or solutions. Like the solution NMR techniques more familiar to most chemists and biologists, solid-state NMR provides valuable information about the molecular structure, molecular motions and other properties of samples under study, but does not require solubility or crystallinity. The application of solid-state NMR to assemblies of proteins or short amino-acid chains called peptides is a rapidly growing area of research, with amyloid fibrils being one of the main targets. From the standpoint of methodology alone, the new structures represent a major triumph.

One of the main problems facing structural studies of amyloid fibrils is that these assemblies are typically polymorphic — they can adopt several distinct molecular structures, which often depend on subtle variations in fibril growth conditions4,5. This polymorphism, together with the fact that roughly half of the amino acids in Aβ42 are hydrophobic, makes it hard to prepare the milligram-scale, structurally homogeneous Aβ42 fibril samples required for solid-state NMR.

To overcome this problem, Colvin et al. and Wälti et al. grew their Aβ42 fibrils in aqueous solutions with different combinations of pH, temperature and ionic strength, to optimize structural homogeneity. (The method used by Colvin and colleagues is described in detail in ref. 6.) Wälti et al. also adopted an approach previously developed4 to prepare fibrils of the 40-residue version of the protein (Aβ40) — fibrils were grown in several successive rounds, each seeded from the last, to purify a single predominant structure from an initial mixture of polymorphs. Despite differences in sample-preparation conditions, the Aβ42 fibril structures determined by the two groups are almost identical. It seems, therefore, that this Aβ42 structure is thermodynamically stable and forms efficiently in a range of conditions.

So what is the structure of Aβ42 fibrils? Both groups find that their Aβ42 molecules adopt a roughly S-shaped conformation, comprising short β-strand segments linked by bends. Molecules stack directly on top of one another in the direction of fibril growth, forming in-register stacks of parallel cross-β subunits — structures in which β-strands of neighbouring molecules are linked by hydrogen bonds along the growth axis7. Each fibril contains two such subunits, arranged with two-fold symmetry about the growth axis (Fig. 1a).

Figure 1: Molecular structures of amyloid fibrils.
figure1

Colvin et al.1 and Wälti et al.2 used solid-state nuclear magnetic resonance to define similar structures of fibrils formed by the 42-amino-acid version of amyloid-β protein (Aβ42). a, As this cartoon representation of Colvin and colleagues' structure (from Protein Data Bank file 5KK3) shows, the groups find that individual monomers form S-shapes that comprise short β-strand segments (arrows) linked by bends, and that stack in two parallel subunits to form fibrils. b, A comparison of one Aβ42 monomer with a monomer from a fibril formed by the 40-amino-acid version of the protein9 (Aβ40, Protein Data Bank file 2M4J) indicates that the two probably cannot stack together. Dashed ellipses indicate examples of differences in amino-acid side-chain interactions, for phenylalanine-19 (F19) and lysine-28 (K28). Blue, red and yellow regions indicate nitrogen, oxygen and sulfur atoms, respectively. Residues 1–13 are omitted.

The cross-β-subunit structures determined by Colvin et al. and Wälti et al. agree well with the findings of a previous study8. However, this earlier work did not show how subunits interact to produce two-fold symmetry and did not define the conformation of amino-acid residues 34–36 unambiguously. The excellent overall agreement between these three independent studies, which used different strategies for labelling their samples, different combinations of solid-state NMR measurements and different molecular-modelling approaches, makes the results highly reliable.

40 is more abundant than Aβ42 in the healthy human brain, but is less hydrophobic and so less prone to aggregation. Like Aβ42, Aβ40 fibrils have been shown4,9,10 by solid-state NMR to contain in-register, parallel cross-β subunits, arranged with either two-fold or three-fold symmetry. But many details of the molecular conformations, and the interactions within and between molecules in Aβ40 and Aβ42 fibrils are quite different (Fig. 1b). It seems that these structural differences — especially interactions that involve residues 41 and 42, which are absent from Aβ40 — would make it impossible for Aβ40 to form stable fibrils that are similar to the newly determined Aβ42 structure.

In addition, comparison of the structures reveals that the carboxy-terminal segment of Aβ is exposed on the surface in fibrils of Aβ42, but is buried in the core of Aβ40 fibrils4,9,10. Differences in surface composition and structure may affect the neurotoxicity of Aβ40 and Aβ42 fibrils, conferring different interactions with neuronal membranes, membrane-bound receptor proteins or the cerebral vasculature; different abilities to stimulate inflammation; and different properties in terms of recognition by antibodies. These structural properties provide a likely explanation for the observation that Aβ42 fibril fragments cannot be extended by Aβ40 molecules8 — a process called cross-seeding. An absence of cross-seeding might affect how Aβ40 and Aβ42 fibrils propagate in brain tissue in Alzheimer's disease, determining whether the two species act independently or in concert.

Specific structural features revealed by the authors' solid-state NMR studies may enable the design of chemical compounds that either inhibit fibril formation or bind tightly to fibrils, and that can distinguish between Aβ40 and Aβ42. Such compounds are of potential interest for the prevention or treatment of Alzheimer's disease, for diagnostic imaging and for research into the roles of the two peptides in the disease.

Finally, both groups prepared the Aβ42 fibrils for their experiments in vitro. Does the same structure develop naturally in human brain tissue, and do other Aβ42 fibril polymorphs also develop? Wälti et al. show that their fibrils are bound by the same panel of antibodies that recognize Aβ deposits in brain tissue, providing evidence for their biomedical relevance. Solid-state NMR measurements on Aβ42 fibrils derived from brain tissue, as have been reported for Aβ40 fibrils10, would be a sensible direction for future research. Footnote 1

Notes

  1. 1.

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Correspondence to Robert Tycko.

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Tycko, R. Structure of aggregates revealed. Nature 537, 492–493 (2016). https://doi.org/10.1038/nature19470

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