Oligomerization and fibril assembly of the amyloid-β protein

In this chapter, we attempt to analyze the evolution of the amyloid-beta (A beta) molecular structure from its inception as part of the A beta precursor protein to its release by the secretases and its extrusion from membrane into an aqueous environment. Biophysical studies suggest that the A beta peptide sustains a series of transitions from a molecule rich in alpha-helix to a molecule in which beta-strands prevail. It is proposed that initially the extended C-termini of two opposing A beta dimers form an antiparallel beta-sheet and that the subsequent addition of dimers generates a helical A beta protofilament. Two or more protofilaments create a strand in which the hydrophobic core of the beta-sheets is shielded from the aqueous environment by the N-terminal polar domains of the A beta dimers. Once the nucleation has occurred, the A beta filament grows in length by the addition of dimers or tetramers. (C) 2000 Elsevier Science B.V. All rights reserved.