Molecular structure of an N-terminal phosphorylated ?-amyloid fibril.

ABSTRACT: The structural polymorphism in ?-amyloid (A?) 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? (PTM-A?) subtypes. Although many PTM-A?s were shown to accelerate the fibrillation process, increase neuronal cytotoxicity of aggregates, or enhance the stability of fibrils, the contribution of PTM-A?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? (pS8-A?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?40 fibrils may potentially dominate the polymorphisms in the mixture of wild-type and phosphorylated A? deposits. Our results imply that A? subtypes with "seeding-prone" properties may influence the polymorphisms of amyloid plaques through the cross-seeding process.

SUBMITTER: Hu ZW 

PROVIDER: S-EPMC6561245 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature