Mechanism of Nucleated Conformational Conversion of Aβ42

Soluble oligorners and protofibrils of the A beta 42 peptide are neurotoxic intermediates in the conversion of monomeric A beta 42 into the amyloid fibrils associated with Alzheimer's disease. Nuclear magnetic resonance and Fourier transform infrared spectroscopy, along with single-touch atomic force microscopy, are used to establish the structural transitions involved in fibril formation. We show that under conditions favorable for the nucleated conformation conversion, the A beta 42 peptide aggregates into largely unstructured low-molecular weight (MW) oligomers that are able to stack to form high-MW oligomers and to laterally associate to form protofibrils. beta-Sheet secondary structure develops during the irreversible lateral association of the oligomers. The first step in this conversion is the formation of an antiparallel beta-hairpin stabilized by intramonomer hydrogen bonding. The antiparallel beta-hairpins then associate into a cross beta-sheet structure with parallel and in-register beta-strands having intermonomer hydrogen bonding.