Molecular structure of an N-terminal phosphorylated β-amyloid fibril

The structural polymorphism in beta-amyloid (A beta) plaques from Alzheimer disease (AD) has been recognized as an important pathological factor. Plaques from sporadic AD patients contain fibrillar deposits of various amyloid proteins/peptides, including posttranslational modified A beta (PTM-A beta) subtypes. Although many PTM-A beta s were shown to accelerate the fibrillation process, increase neuronal cytotoxicity of aggregates, or enhance the stability of fibrils, the contribution of PTM-A beta s to structural polymorphisms and their pathological roles remains unclear. We report here the NMR-based structure for the Ser-8-phosphorylated 40-residue A beta (pS8-A beta 40) fibrils, which shows significant difference to the wild-type fibrils, with higher cross-seeding efficiency and thermodynamic stability. Given these physicochemical properties, the structures originated from pS8-A beta 40 fibrils may potentially dominate the polymorphisms in the mixture of wild-type and phosphorylated A beta deposits. Our results imply that A beta subtypes with seeding-prone properties may influence the polymorphisms of amyloid plaques through the cross-seeding process.