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A new era for understanding amyloid structures and disease


The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-β structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention.

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The authors thank members of their laboratories and their colleagues for many helpful discussions while preparing this Review. M.G.I., M.P.J., E.W.H., N.A.R and S.E.R. acknowledge funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC grant agreement no. 322408 and from the Wellcome Trust (092896MA and 204963).

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All authors wrote the manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to Sheena E. Radford.



Fibrils formed from proteins, marked by a characteristic cross-β organization with an ~4.7–4.8 Å repeat running down the fibril axis.


The structural motif consisting of β-strands organized perpendicular to the axis of a fibril and stabilized by inter-strand hydrogen bonds and dry steric zipper interfaces between adjacent β-sheets.


Proteins that assist in the folding, unfolding, assembly or disassembly of other macromolecular structures.


A structural component of an amyloid fibril with a cross-β structure that twists together with one or more additional protofibrils to form a mature amyloid fibril.


The smallest units that make up an amyloid fibril, generally single copies of the precursor protein.


A class of diseases associated with the formation of amyloid fibrils, tangles and plaques, although the causative agents of disease have yet to be determined definitively.


A class of infectious amyloid fibrils.

Age of onset

The age at which a patient first presents symptoms. For amyloid-associated disorders, this is not necessarily directly correlated with fibril load: high fibril loads may be asymptomatic, whereas low fibril loads may lead to severe symptoms.


A dialysis-based filtration treatment that acts to replace kidney function in patients experiencing kidney failure.

Phase separation

A process driven by liquid–liquid demixing, leading to a liquid mixture separating into individual components. In cells, this can lead to localized increased concentration and supersaturation of biological molecules.

Intrinsically disordered proteins

Proteins that lack a fixed or ordered 3D structure.

Fibril load

A measure of the total amount of amyloid fibril within a sample or patient.

Native protein

The properly assembled form of a protein required for functionality.


The distance it takes a fibril to achieve 180° of rotation. Crossover appears as the distance between the two narrowest points on a 2D EM or atomic force microscopy image of a twisted fibril.

Long-term potentiation

A persistent increase in synaptic strength after stimulation of the synapse.

Pi-stacking interactions

Attractive, noncovalent interactions between aromatic rings (phenylalanine, Tyr and Trp in proteins).


A group of microorganisms that have adhered to each other and/or a surface.

Gram-positive organisms

Bacteria that possess a peptidoglycan-containing cell wall, which can be positively stained with crystal violet dye, known as Gram stain.


The same protein can assemble into amyloid fibrils that have different arrangements of subunits in the fibril, numbers of protofilaments, widths and/or crossover distances.

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Further reading

Fig. 1: Progression of amyloid structure research over close to 400 years that has culminated in the first atomic structures of amyloid fibrils.
Fig. 2: Schematic of amyloid formation.
Fig. 3: Amyloid aggregates can cause cell disruption by a variety of mechanisms.
Fig. 4: Structural motifs that stabilize amyloid fibrils.
Fig. 5: Subunit packing in amyloid fibrils.
Fig. 6: How changes in primary sequence affect amyloid disease.