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1. Molecular insights into the surface-catalyzed secondary nucleation of amyloid-β ₄₀ (Aβ ₄₀ ) by the peptide fragment Aβ _16–22

   https://doi.org/10.1126/sciadv.aav8216  

   Bunce, Samuel J.; Wang, Yiming; Stewart, Katie L.; Ashcroft, Alison E.; Radford, Sheena E.; Hall, Carol K.; Wilson, Andrew J. (June 2019, Science Advances)

   Understanding the structural mechanism by which proteins and peptides aggregate is crucial, given the role of fibrillar aggregates in debilitating amyloid diseases and bioinspired materials. Yet, this is a major challenge as the assembly involves multiple heterogeneous and transient intermediates. Here, we analyze the co-aggregation of Aβ 40 and Aβ 16–22 , two widely studied peptide fragments of Aβ 42 implicated in Alzheimer’s disease. We demonstrate that Aβ 16–22 increases the aggregation rate of Aβ 40 through a surface-catalyzed secondary nucleation mechanism. Discontinuous molecular dynamics simulations allowed aggregation to be tracked from the initial random coil monomer to the catalysis of nucleation on the fibril surface. Together, the results provide insight into how dynamic interactions between Aβ 40 monomers/oligomers on the surface of preformed Aβ 16–22 fibrils nucleate Aβ 40 amyloid assembly. This new understanding may facilitate development of surfaces designed to enhance or suppress secondary nucleation and hence to control the rates and products of fibril assembly. 

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2. Exploring the interplay between fibrillization and amorphous aggregation channels on the energy landscapes of tau repeat isoforms

   https://doi.org/10.1073/pnas.1921702117  

   Chen, Xun; Chen, Mingchen; Schafer, Nicholas P.; Wolynes, Peter G. (February 2020, Proceedings of the National Academy of Sciences)

   null (Ed.)

   Filaments made up of different isoforms of tau protein are associated with a variety of neurodegenerative diseases. Filaments made up of the 4R-tau isoform, which has four repeat regions (R1 to R4), are found in patients suffering from Alzheimer’s disease, while filaments made of the 3R-tau isoform, which contains only three repeat units (R1, R3, and R4), are found in patients with Pick’s disease (frontotemporal dementia). In this work, a predictive coarse-grained protein force field, the associative memory water-mediated structure and energy model (AWSEM), is used to study the energy landscapes of nucleation of the two different fibrils derived from patients with Pick’s and Alzheimer’s diseases. The landscapes for nucleating both fibril types contain amorphous oligomers leading to branched structures as well as prefibrillar oligomers. These two classes of oligomers differ in their structural details: The prefibrillar oligomers have more parallel in-register β-strands, which ultimately lead to amyloid fibrils, while the amorphous oligomers are characterized by a near random β-strand stacking, leading to a distinct amorphous phase. The landscape topography suggests that there must be significant structural reordering, or “backtracking,” to transit from the amorphous aggregation channel to the fibrillization channel. Statistical mechanical perturbation theory allows us to evaluate the effects of changing concentration on the aggregation free-energy landscapes and to predict the effects of phosphorylation, which is known to facilitate the aggregation of tau repeats. 

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3. Self-Assembly of Amyloid Fibrils into 3D Gel Clusters versus 2D Sheets

   https://doi.org/10.3390/biom13020230  

   Karunarathne, Kanchana; Bushra, Nabila; Williams, Olivia; Raza, Imad; Tirado, Laura; Fakhre, Diane; Fakhre, Fadia; Muschol, Martin (February 2023, Biomolecules)

   The deposition of dense fibril plaques represents the pathological hallmark for a multitude of human disorders, including many neurodegenerative diseases. Fibril plaques are predominately composed of amyloid fibrils, characterized by their underlying cross beta-sheet architecture. Research into the mechanisms of amyloid formation has mostly focused on characterizing and modeling the growth of individual fibrils and associated oligomers from their monomeric precursors. Much less is known about the mechanisms causing individual fibrils to assemble into ordered fibrillar suprastructures. Elucidating the mechanisms regulating this “secondary” self-assembly into distinct suprastructures is important for understanding how individual protein fibrils form the prominent macroscopic plaques observed in disease. Whether and how amyloid fibrils assemble into either 2D or 3D supramolecular structures also relates to ongoing efforts on using amyloid fibrils as substrates or scaffolds for self-assembling functional biomaterials. Here, we investigated the conditions under which preformed amyloid fibrils of a lysozyme assemble into larger superstructures as a function of charge screening or pH. Fibrils either assembled into three-dimensional gel clusters or two-dimensional fibril sheets. The latter displayed optical birefringence, diagnostic of amyloid plaques. We presume that pH and salt modulate fibril charge repulsion, which allows anisotropic fibril–fibril attraction to emerge and drive the transition from 3D to 2D fibril self-assembly. 

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4. Thermodynamic phase diagram of amyloid-β (16–22) peptide

   https://doi.org/10.1073/pnas.1819592116  

   Wang, Yiming; Bunce, Samuel J.; Radford, Sheena E.; Wilson, Andrew J.; Auer, Stefan; Hall, Carol K. (February 2019, Proceedings of the National Academy of Sciences)

   The aggregation of monomeric amyloid β protein (Aβ) peptide into oligomers and amyloid fibrils in the mammalian brain is associated with Alzheimer’s disease. Insight into the thermodynamic stability of the Aβ peptide in different polymeric states is fundamental to defining and predicting the aggregation process. Experimental determination of Aβ thermodynamic behavior is challenging due to the transient nature of Aβ oligomers and the low peptide solubility. Furthermore, quantitative calculation of a thermodynamic phase diagram for a specific peptide requires extremely long computational times. Here, using a coarse-grained protein model, molecular dynamics (MD) simulations are performed to determine an equilibrium concentration and temperature phase diagram for the amyloidogenic peptide fragment Aβ 16–22 . Our results reveal that the only thermodynamically stable phases are the solution phase and the macroscopic fibrillar phase, and that there also exists a hierarchy of metastable phases. The boundary line between the solution phase and fibril phase is found by calculating the temperature-dependent solubility of a macroscopic Aβ 16–22 fibril consisting of an infinite number of β-sheet layers. This in silico determination of an equilibrium (solubility) phase diagram for a real amyloid-forming peptide, Aβ 16–22 , over the temperature range of 277–330 K agrees well with fibrillation experiments and transmission electron microscopy (TEM) measurements of the fibril morphologies formed. This in silico approach of predicting peptide solubility is also potentially useful for optimizing biopharmaceutical production and manufacturing nanofiber scaffolds for tissue engineering. 

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5. N -Amino peptide scanning reveals inhibitors of Aβ ₄₂ aggregation

   https://doi.org/10.1039/D0RA02009E  

   Tillett, Khalilia C.; Del Valle, Juan R. (April 2020, RSC Advances)

   The aggregation of amyloids into toxic oligomers is believed to be a key pathogenic event in the onset of Alzheimer's disease. Peptidomimetic modulators capable of destabilizing the propagation of an extended network of β-sheet fibrils represent a potential intervention strategy. Modifications to amyloid-beta (Aβ) peptides derived from the core domain have afforded inhibitors capable of both antagonizing aggregation and reducing amyloid toxicity. Previous work from our laboratory has shown that peptide backbone amination stabilizes β-sheet-like conformations and precludes β-strand aggregation. Here, we report the synthesis of N -aminated hexapeptides capable of inhibiting the fibrillization of full-length Aβ 42 . A key feature of our design is N -amino substituents at alternating backbone amides within the aggregation-prone Aβ 16–21 sequence. This strategy allows for maintenance of an intact hydrogen-bonding backbone edge as well as side chain moieties important for favorable hydrophobic interactions. An N -amino scan of Aβ 16–21 resulted in the identification of peptidomimetics that block Aβ 42 fibrilization in several biophysical assays. 

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