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

Amyloid beta (A beta) peptides are a major contributor to Alzheimer's disease. They 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 annular protofibrils (sAPFs) and beaded annular protofibrils (bAPFs), 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 similar to 32 monomers. Here we propose a range of concentric beta-barrel models and compare their dimensions to image-averaged electron micrographs of both bAPFs and 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 bAPRs 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.