Structures of brain-derived 42-residue amyloid-β fibril polymorphs with unusual molecular conformations and intermolecular interactions

Fibrils formed by the 42-residue amyloid-beta peptide (A beta 42), 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 A beta 42 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-beta subunit pairs within a single filament. Despite these differences, A beta 42 molecules adopt a common S-shaped conformation in all previously described high-resolution A beta 42 fibril structures. Here we report two cryo-EM-based structures of A beta 42 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 nu-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 upsilon-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 A beta 42 fibril samples. These results demonstrate that A beta 42 fibrils can exhibit a greater range of structural variations than seen in previous studies.

Automated summary

The study finds that A beta 42 fibrils exhibit polymorphism and have different molecular structures. Two qualitatively different structures of A beta 42 fibrils are reported using cryo-EM methods, derived from AD brain tissue. These results demonstrate a greater range of structural variations in A beta 42 fibrils than seen in previous studies.