ArticleProceedings of the National Academy of Sciences of the United States of America2023
Structures of brain-derived 42-residue amyloid-β fibril polymorphs with unusual molecular conformations and intermolecular interactions.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 57 citations in OpenAlex.
- Brain-seeded 42-residue Amyloid-β Fibrils That Resemble Fibrils Directly Extracted From Alzheimer's Disease Brain Tissue.Journal of molecular biology · 2026Article
- Polymorphic structures of rapidly twisting 40-residue amyloid-β fibrils.Biophysical journal · 2026Article
- Structural Hierarchy and Maturation of Amyloid Fibrils Revealed by Interface Descriptor Analysis.Journal of chemical information and modeling · 2026Article
- Multipathway Aggregation Drives Concentration-Dependent Amyloid Polymorphism and Time-Dependent Morphological Evolution.The journal of physical chemistry letters · 2026Article
- Distinct amyloid-β filament fold in individuals with APP Flemish mutation.Nature structural & molecular biology · 2026Article
- Temperature-Dependent Dynamics of Aβ42 and α-Synuclein Monomers and Early Oligomerization of Aβ42: Shared Residues Mediate Intra- and Intermolecular β-Sheets.ACS chemical neuroscience · 2026Article
- The Monomeric Conformational Ensembles of Aβ40 and Aβ42 Encode Their Differential Amyloid Aggregation Propensity.The journal of physical chemistry. B · 2026Article
- Atomic structures of medin and Aβ fibrils reveal polymorphic remodeling in mixed amyloid systems.Nature communications · 2026Article
- Controlled Seeding of β-Amyloid Fibrillation Reveals Propagation of Structural Polymorphisms in Cellular Environments.Biochemistry · 2026Article
- Polymorphic structures of rapidly twisting 40-residue amyloid-β fibrils.bioRxiv : the preprint server for biology · 2026Article
- In vitro, cellular and in vivo studies of amyloid oligomers structure and toxicity: Challenges and advances.Protein science : a publication of the Protein Society · 2026Review
- Cracking the code of native amyloid fibrils: advances and next steps to enable pathology-informed therapeutic and diagnostic.Nature structural & molecular biology · 2026Review
- Unraveling Alzheimer's complexity with a distinct AβNature chemical biology · 2026Article
- Digging Deep into Alzheimer Disease: How Electron Microscopy Helps Elucidating Its Pathogenesis.Cellular and molecular neurobiology · 2026Review
- Differentiating Alzheimer's Aβ Isoforms Coaggregated in Cerebrospinal Fluid via Single-Particle Imaging.ACS chemical neuroscience · 2026Article
- Time-resolved solid-state nuclear magnetic resonance studies of amyloid-β oligomer formation.Methods in enzymology · 2026Review
- Atomic Structure of GNNQQNY Nanocrystals: A Validated Approach for Polymorphic Amyloids.The journal of physical chemistry letters · 2025Article
- Prions and protein aggregates as pathogens, self-propagating structures, biomarkers, and therapeutic targets.Microbiology and molecular biology reviews : MMBR · 2025Review
- Structural reconstruction of individual filaments in AβCommunications chemistry · 2025Article
- Single-fibril Förster resonance energy transfer imaging and deep learning reveal concentration dependence of amyloid β 42 aggregation pathways.PNAS nexus · 2025Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Fibrils formed by the 42-residue amyloid-β peptide (Aβ42), a main component of amyloid deposits in Alzheimer's disease (AD), are known to be polymorphic, i.e., to contain multiple possible molecular structures. Previous studies of Aβ42 fibrils, including fibrils prepared entirely in vitro or extracted from brain tissue and using solid-state NMR (ssNMR) or cryogenic electron microscopy (cryo-EM) methods, have found polymorphs with differences in amino acid sidechain orientations, lengths of structurally ordered segments, and contacts between cross-β subunit pairs within a single filament. Despite these differences, Aβ42 molecules adopt a common S-shaped conformation in all previously described high-resolution Aβ42 fibril structures. Here we report two cryo-EM-based structures of Aβ42 fibrils that are qualitatively different, in samples derived from AD brain tissue by seeded growth. In type A fibrils, residues 12 to 42 adopt a ν-shaped conformation, with both intra-subunit and intersubunit hydrophobic contacts to form a compact core. In type B fibrils, residues 2 to 42 adopt an υ-shaped conformation, with only intersubunit contacts and internal pores. Type A and type B fibrils have opposite helical handedness. Cryo-EM density maps and molecular dynamics simulations indicate intersubunit K16-A42 salt bridges in type B fibrils and partially occupied K28-A42 salt bridges in type A fibrils. The coexistence of two predominant polymorphs, with differences in N-terminal dynamics, is supported by ssNMR data, as is faithful propagation of structures from first-generation to second-generation brain-seeded Aβ42 fibril samples. These results demonstrate that Aβ42 fibrils can exhibit a greater range of structural variations than seen in previous studies.
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