Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue

Amyloid-beta (A beta) 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 A beta peptides (A beta 40), 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 A beta 40 fibril polymorph from typical AD patients. The structure, which has 2.8-angstrom resolution according to standard criteria, differs qualitatively from all previously described A beta fibril structures, both in its molecular conformations and its organization of cross-beta subunits. Unique features include twofold screw symmetry about the fibril growth axis, despite an MPL value that indicates three A beta 40 molecules per 4.8-angstrom beta-sheet spacing, a fourlayered architecture, and fully extended conformations for molecules in the central two cross-beta layers. The cryoEM density, ssNMR data, and MPL data are consistent with beta-hairpin conformations for molecules in the outer cross-beta layers. Knowledge of this brainderived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility.