Gremer L, Schölzel D, Schenk C, Reinartz E, Labahn J, Ravelli RB, Tusche M, Lopez-Iglesias C, Hoyer W, Heise H, Willbold D, Schröder GF. Fibril structure of amyloid-β(1-42) by cryo-electron microscopy. Science. 2017 Oct 6;358(6359):116-119. Epub 2017 Sep 7 PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. This is an important paper, demonstrating that detailed molecular structural information about Aβ fibrils can be obtained from cryoEM. Other labs have attempted this in earlier publications, but with less success. The success of this work by Gremer et al. is due to recent improvements in cryoEM technology as well as their selection of in vitro fibril growth conditions to produce structurally homogeneous Aβ fibrils that are well suited for cryoEM analysis.

    Up to this point, detailed structural information about amyloid fibrils has come primarily from solid-state NMR measurements. The structure determined by Gremer et al. is different from structures of 42-residue Aβ fibrils that have been reported previously by solid-state NMR labs. But the fibril growth conditions are different, so I would not expect the structures to be the same, given the ability of Aβ peptides to form a variety of fibril polymorphs. The new cryoEM-based structure is similar in many respects to solid state NMR-based structures for other 40- and 42-residue Aβ fibril polymorphs that have been reported previously, so the work of Gremer et al. does not change our overall understanding of fibril structures. It is important to recognize that there is no contradiction between the cryoEM results and solid-state NMR results. Different labs are simply studying different polymorphs.

    Gremer et al. also report solid-state NMR spectra of their fibrils. These spectra are not the same as spectra of in vitro 42-residue Aβ fibrils that have been characterized structurally by solid state NMR. The solid-state NMR spectra of Gremer et al. are also not the same as spectra of 42-residue Aβ derived from brain tissue of Alzheimer's disease patients, as reported by Qiang et al. (2017). 

    The work of Gremer et al. is an important contribution to progress on molecular structural aspects of amyloid formation, but much work remains to be done on structures of fibrils that develop in the AD brain and on possible connections between structural variations and variations in the disease.

    References:

    Qiang W, Yau WM, Lu JX, Collinge J, Tycko R. Structural variation in amyloid-β fibrils from Alzheimer's disease clinical subtypes. Nature. 2017 Jan 12;541(7636):217-221. Epub 2017 Jan 4 PubMed.

    View all comments by Robert Tycko

  2. Another example of what the "resolution revolution" in cryo EM is giving us. In combination with rapidly developing image-processing algorithms, the new direct electron detectors allow us to finally get high-resolution views of nearly all disease-causing amyloids. 

    Sample homogeneity and the presence of polymorphic assemblies in any given sample are still stumbling blocks in some cases, but the recent examples of brain-derived PHFs and in vitro assembled Aβ1-42 fibrils lead the way. It took a long time to get to this stage, but the wait was definitely worth it.

    View all comments by Holger Wille

  3. This is great work, representing a major advance in the structural understanding of Aβ fibrils. The structure was determined by cryo-EM at a resolution of 4 Å and gives detailed information about the conformation of all residues, including the N-terminus, which is part of the cross-ß-structure. Thus, the structure supports the idea that the N-terminus plays a role not only in the initial aggregation processes, but also in the stabilization of distinct fibril topologies.

    View all comments by Heinrich Sticht

  4. Very impressive work at high resolution. Particularly interesting is the well-structured N-terminus. I think this will not be the last polymorph of Aβ that we will see in high resolution, featuring altered salt bridges and hydrophobic contacts.

    View all comments by Daniel Huster

  5. The new structure of Aβ1-42 is highly interesting, as it shows a different polymorph compared to the ones investigated in previous studies. Given that these various structures were obtained under rather different conditions of fibril formation, it is now a major task to determine which of these states faithfully remodels the structures present in a patient's brain.

    View all comments by Fändrich Marcus

  6. Well done! This is a great piece of work at a high resolution providing us with further insights into the structural variety that can be observed with Aβ in an aggregated state. Now it would be interesting to correlate biological function, e.g., spreading in vivo with the distinct structural motifs. Such an endeavor could eventually lead to a structure activity relationship of Aβ aggregates describing better the complex and polymorphic situation found in AD patients.

    View all comments by Jan Stoehr

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. Amyloid-β Fibril Structure Bares All