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| Title | Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue. |
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| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 118, Issue 4, Year 2021 |
| Publish date | Jan 26, 2021 |
 Authors | Ujjayini Ghosh / Kent R Thurber / Wai-Ming Yau / Robert Tycko /  |
| PubMed Abstract | Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer's disease (AD). We report ...Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer's disease (AD). We report the molecular structure of a specific fibril polymorph, formed by 40-residue Aβ peptides (Aβ40), that is derived from cortical tissue of an AD patient by seeded fibril growth. The structure is determined from cryogenic electron microscopy (cryoEM) images, supplemented by mass-per-length (MPL) measurements and solid-state NMR (ssNMR) data. Previous ssNMR studies with multiple AD patients had identified this polymorph as the most prevalent brain-derived Aβ40 fibril polymorph from typical AD patients. The structure, which has 2.8-Å resolution according to standard criteria, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformations and its organization of cross-β subunits. Unique features include twofold screw symmetry about the fibril growth axis, despite an MPL value that indicates three Aβ40 molecules per 4.8-Å β-sheet spacing, a four-layered architecture, and fully extended conformations for molecules in the central two cross-β layers. The cryoEM density, ssNMR data, and MPL data are consistent with β-hairpin conformations for molecules in the outer cross-β layers. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility. |
 External links | Proc Natl Acad Sci U S A / PubMed:33431654 / PubMed Central |
| Methods | EM (helical sym.) / NMR (solid-state) |
| Resolution | 2.77 Å |
| Structure data | EMDB-21501, PDB-6w0o: |
| Source |
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 Keywords | PROTEIN FIBRIL /  amyloid-beta / Alzheimer's disease |
