. Cryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer's brain tissue. Nat Commun. 2019 Oct 29;10(1):4760. PubMed.


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  1. This paper was a lot of fun to read. The authors describe the structure of Aβ amyloid filaments that were extracted from meningeal Alzheimer’s brain tissue. As we previously also observed for tau filaments, the Aβ filaments form different structures in the brain from those obtained through in vitro aggregation methods.

    Interestingly, as some of these authors also described for serum amyloid A protein from human systemic AA amyloidosis, the Aβ filaments are right-handed, despite amyloid filaments having a natural tendency to be left-handed due to the natural twist of β-strands.

    The authors also found polymorphism in the Aβ filaments, which again is reminiscent of the polymorphism found in tau, as the same protofilaments can pack against each other in different ways. For Aβ, filaments with one, two, or three protofilaments were observed. Molecular details of the structure remain at large due to the somewhat limited resolution, which can be explained by the limited mass of the filament per unit length.

    This study confirms the importance of structure determination on diseased tissue samples, and provides a first glimpse into the thus-far uncharacterised structures of Aβ filaments in Alzheimer's disease. In the future, it will be interesting to see whether, in disease, Aβ filaments are as structurally diverse as tau filaments have been shown to be.

    View all comments by Sjors Scheres
  2. This work by Jucker and Fändrich is a very important step forward in the structural biology of Aβ, since the amyloid has been purified from human AD material. This is the first structure of its kind (a solid state NMR structure of Aβ(1-40) has been determined before from seeded material using purified brain homogenate by the Tycko group at NIH).

    Highly important to mention is the purification procedure. It is based on an old procedure from Pras et al., 1968, which is apparently based on another purification protocol from Cohen's group. Unfortunately, the details of the present purifications are not given, but the purification is based on water solubility, which is indeed gentle.

    The structure is entirely different from previous, in vitro-derived ones. At the mesosopic scale, it is right-hand twisted and not left-hand twisted, as most of the other fibrils. At the atomic structure, an entire different fold is present, which also includes different segments in the sequence (starting from residue 2, ending already at residue 37). It has a rather large interface between two molecules, etc. It is amazing to see the vast structural diversity of an Aβ amyloid.

    For me, we are at the beginning of the structural biology of amyloid. There are most likely many, many polymorphs that depend on the aggregation conditions. For example, in the case of α-synuclein, there are two very distinct polymorphs likely to be attributable to whether there is phosphate in the buffer or not. Furthermore, based on thermodynamics, all the polymorphs should be present in a sample, but just at different concentrations. Depending on the environment, one polymorph is more present than others because it replicates faster.

    In the AD-derived amyloid presented in this study, all three patients show the same set of polymorphs, indicating a common origin. On the other hand, it could be also that the purification protocol did select this specific polymorph.


    . The characterization of soluble amyloid prepared in water. J Clin Invest. 1968 Apr;47(4):924-33. PubMed.

    View all comments by Roland Riek
  3. This structure is in fact quite different from the Aβ40 fibrils grown in vitro (from incubation of synthetic or expressed Aβ40 in aqueous), and also different from a previously published structure of ex vivo fibrils by Tycko et al. The quaternary interface involves two extended β-strands (K16-E22 and A30-M35). These two strands are usually folded to form an intramolecular interface in other structures. Also, the N-terminus looks more ordered with a third extended β-sheet.

    The implication of this work, in my opinion, is a clear demonstration that the Aβ fibrils are polymorphic at the molecular level in patients. The origin and the biological significance of such polymorphisms are unclear at this point but worth studying. Also, as pointed by the authors in the discussion, the presence of mutations and modifications in Aβ sequences will have non-negligible influences on the molecular structures of resulting fibrils and may also contribute to the time evolution of polymorphisms.

    View all comments by Wei Qiang

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