The amyloid concentric β-barrel hypothesis: Models of amyloid beta 42
oligomers and annular protofibrils
Abstract
Amyloid beta (Aβ) 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 Aβ42; some of
which have antiparallel β-sheets. Previously, our group proposed
molecular models of Aβ42 hexamers in which the C-terminus third of the
peptide (S3) forms an antiparallel 6-stranded β-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 Aβ42
tetramers and octamers, and NMR studies have been reported for oligomers
composed of ~ 32 monomers. Here we propose a range of
concentric β-barrel models and compare their dimensions to
image-averaged electron micrographs of both beaded annular protofibrils
(bAPFs) and smooth annular protofibrils (sAPFs) of Aβ42. 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 β-barrel is shielded on one or both sides by β-barrels
formed from S1 and S2 segments.