Molecular architecture of amyloid forming peptides: Amyloid-beta (1--42) and prion protein (118--135)

Amyloid lesions found in several neurodegenerative and systemic diseases result from the alternative folding of cellular proteins into toxic aggregates. In particular, aggregation of the amyloid-beta (Abeta) peptide has long been posited to be the primary causative agent for Alzheimer's disease pathology. In this study, high resolution 13C solid-state NMR spectroscopy was used to identify molecular contacts in fibrils and pre-fibrillar oligomers formed from the Abeta(1-42) peptide. The hydrophobic core of Abeta(1-42) fibrils consists of a beta-hairpin motif with Phe19 opposite to Leu34 and Gln15 opposite to Gly37. The individual beta-strands within a beta-sheet were found to have a parallel and in-register orientation with a staggered, domain-swapped architecture. In soluble oligomers of Abeta(1-42) stabilized at 4°C, the peptide has a similar beta-hairpin structure with the same Phe19-Leu34 contact. However, the beta-strands do not have a parallel and in-register orientation and do not have a staggered domain-swapped architecture. When the Abeta42 stable oligomers are incubated at 37°C, they condense and elongate to form fibrils, as visualized using a combination of electron and atomic force microscopies. Stable oligomers of Abeta42 are significantly more toxic than fibrils when applied to primary mouse cortical neurons. The results indicate that pre-fibrillar oligomers of Abeta42, which have a defined beta-hairpin structure, nucleate the formation of parallel and in-register domain swapped fibrils with diminished toxicity. A similar analysis was used to investigate the molecular packing arrangement of aggregates formed form the hydrophobic core of human prion protein, PrP (118-135). Amyloid fibrils formed from PrP (118-135) have a polymorphic structure where Met129 can pack against Gly127 and Gly131. Importantly, aggregation of both Amyloid-beta (1-42) and prion protein PrP(118-135) can be inhibited by peptide inhibitors designed to block specific side-chain packing arrangements. Structural elucidation along with the development of structure-specific inhibitors may provide new therapeutic strategies towards ameliorating a wide range of amyloid-specific neurodegenerative and systemic pathologies.