Published on Wed Aug 04 2021

The amyloid concentric β-barrel hypothesis: Models of amyloid beta 42 oligomers and annular protofibrils

Guy, H. R., Kayed, R., Durell, S. R.

Amyloid beta (A{beta}) peptides are a major contributor to Alzheimers disease. The most toxic soluble oligomers are formed by A{beta}42; some of which have antiparallel {beta}-sheets. The smaller oligomers have 6, 8, 12, 16, and 18 monomers.

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Abstract

Amyloid beta (A{beta}) peptides, a major contributor to Alzheimers disease, occur in differing lengths, each of which forms a multitude of assembly types. The most toxic soluble oligomers are formed by A{beta}42; some of which have antiparallel {beta}-sheets. Previously, our group proposed molecular models of A{beta}42 hexamers in which the C-terminus third of the peptide (S3) forms an antiparallel 6-stranded {beta}-barrel that is surrounded by an antiparallel barrel formed by the more polar N-terminus (S1) and middle (S2) portions. These hexamers were proposed to act as seeds from which dodecamers, octadecamers, both smooth and beaded annular protofibrils, and transmembrane channels form. Since then, numerous aspects of our models have been supported by experimental findings. Recently, NMR-based structures have been proposed for A{beta}42 tetramers and octamers, and NMR studies have been reported for oligomers composed of ~ 32 monomers. Here we propose a range of concentric {beta}-barrel models and compare their dimensions to image-averaged electron micrographs of both beaded annular protofibrils (bAPFs) and smooth annular protofibrils (sAPFs) of A{beta}42. The smaller oligomers have 6, 8, 12, 16, and 18 monomers. These beads string together to form necklace-like bAPFs. These gradually morph into sAPFs in which a S3 {beta}-barrel is shielded on one or both sides by {beta}-barrels formed from S1 and S2 segments.