Amyloid-β is not the only component of the senile plaques that mark Alzheimer’s disease. Are the others mere bystanders that get caught in a web of Aβ fibrils, or are they more nefarious, instigating growth of these deposits? For the protein islet amyloid polypeptide, new research hints at the latter. Reporting in the June 15 Nature Structural & Molecular Biology, researchers in Germany led by Gunnar Schröder at Forschungszentrum Jülich and Wolfgang Hoyer at Heinrich Heine University, Düsseldorf, describe the first cryoelectron microscopy structure of IAPP fibrils. They bear an uncanny resemblance to those formed by recombinant Aβ in vitro, forming an almost identical S-shaped fold.
The similarity implies that each of these proteins might cross-seed fibrillization of the other, perhaps explaining how IAPP ends up in amyloid plaques. Of course, IAPP can form aggregates of its own. These occur in islet cells in the pancreas and have been linked to Type 2 diabetes, a risk factor for AD.
Hello Again, S Bend. In recombinant Aβ fibrils, monomers from two protofibrils form an S bend at their C terminus (red/yellow). IAPP forms a similar structure (see below). [Courtesy of Gremer et al., Science/AAAS 2017.]
Using cryoEM, Schröder, Hoyer, and colleagues previously solved the structure of a type of fibril formed by Aβ in vitro (Sep 2017 news). It showed itself to be two protofilaments wrapped around each other. Both protofilaments comprised Aβ monomers stacked in a β-sheet conformation. Each monomer formed an L-S shape, with the N-terminus forming the L and the C-terminal end of the S (see image above). Though other structures of recombinant Aβ had been determined by NMR and cryoEM, this was the first to account for all 42 Aβ amino acids. Other structural biologists emphasize, however, that a cryoEM structure of Aβ fibrils isolated from human brain tissue showed a radically different structure with a right-handed twist, which is atypical for β-sheet fibrils. This was of Aβ40, not Aβ42 (Nov 2019 news).
IAPP Amyloid. Cross-sectional view of one IAPP polymorph, which comprises two protofibrils made up of stacked monomers (red and yellow). The monomers form an S-shaped curve similar to that found in fibrils of recombinant Aβ. [Courtesy of Röder, Nature Structural & Molecular Biology.]
Now, co-first authors Christine Röder, Tatsiana Kupreichyk, and colleagues report that the 37 amino acids of synthetic IAPP adopt a similar S-shaped conformation as does recombinant Aβ42. IAPP formed five differently structured fibrils, or polymorphs, in vitro, three of which could be resolved by cryoEM. PM1, which accounted for 90 percent of the fibrils, formed the S shape (see image above). Röder found that the backbones of the IAPP and Aβ fibrils superimposed almost perfectly when in an anti-parallel arrangement, i.e., lying head to tail, not head to head (see image below). Both had been prepared similarly, by allowing fibrils to form at low pH for up to several weeks.
S for Superimpose. The S-shaped structure of IAPP (red) and Aβ (blue) superimpose almost perfectly in an anti-parallel arrangement (left), not so much in parallel (right). [Courtesy of Röder, Nature Structural & Molecular Biology.]
The finding evokes a potential mechanism for cross-seeding. This phenomenon has been proposed to explain the co-occurrence of different amyloids in the brain, including deposits of α-synuclein and TDP-43 alongside amyloid plaques in AD. “The similarity between IAPP and Aβ1–42 fibril folds regarding topology and size might promote cross-seeding at the fibril end, which could further be supported by the sequence similarity of IAPP and Aβ,” write the authors. Previous work showed that IAPP and Aβ, which share some primary amino acid sequences as well as being of similar size, hasten the fibrillization of each other in mouse models (Oskarsson et al., 2015; Moreno-Gonzalez et al., 2017).
Schröder acknowledged that this big idea hinges on structures of Aβ and IAPP obtained in vitro. “It is not clear at this point if these precise structures are disease-associated, since the spectra of disease-related fibril polymorphs have neither been defined for IAPP nor for Aβ42,” he wrote to Alzforum.—Tom Fagan
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- Oskarsson ME, Paulsson JF, Schultz SW, Ingelsson M, Westermark P, Westermark GT. In vivo seeding and cross-seeding of localized amyloidosis: a molecular link between type 2 diabetes and Alzheimer disease. Am J Pathol. 2015 Mar;185(3):834-46. Epub 2015 Feb 17 PubMed.
- Moreno-Gonzalez I, Edwards Iii G, Salvadores N, Shahnawaz M, Diaz-Espinoza R, Soto C. Molecular interaction between type 2 diabetes and Alzheimer's disease through cross-seeding of protein misfolding. Mol Psychiatry. 2017 Jan 3; PubMed.
No Available Further Reading
- Röder C, Kupreichyk T, Gremer L, Schäfer LU, Pothula KR, Ravelli RB, Willbold D, Hoyer W, Schröder GF. Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils. Nat Struct Mol Biol. 2020 Jul;27(7):660-667. Epub 2020 Jun 15 PubMed.