A molecular model of Alzheimer amyloid beta-peptide fibril formation

Polymerization of the amyloid beta (A beta) peptide into protease-resistant fibrils is a significant step in the pathogenesis of Alzheimer's disease. It has not been possible to obtain detailed structural information about th is process with conventional techniques because the peptide has limited sol ubility and does not form crystals. In this work, we present experimental r esults leading to a molecular level model for fibril formation. Systematica lly selected A beta-fragments containing the A beta(16-20) sequence, previo usly shown essential for A beta-A beta binding, were incubated in a physiol ogical buffer. Electron microscopy revealed that the shortest fibril-formin g sequence was A beta(14-23). Substitutions in this decapeptide impaired fi bril formation and deletion of the decapeptide from A beta(1-42) inhibited fibril formation completely. All studied peptides that formed fibrils also formed stable dimers and/or tetramers, Molecular modeling of A beta(14-23) oligomers in an antiparallel beta-sheet conformation displayed favorable hy drophobic interactions stabilized by salt bridges between all charged resid ues. We propose that this decapeptide sequence forms the core of A beta-fib rils, with the hydrophobic C terminus folding over this core. The identific ation of this fundamental sequence and the implied molecular model could fa cilitate the design of potential inhibitors of amyloidogenesis.