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

Significance This work reports the molecular structure formed by a pathologically relevant posttranslational modified β-amyloid (Aβ), the Ser-8-phosphorylated Aβ40 (pS8-Aβ40). The N-terminal structures in pS8-Aβ40 fibril differ significantly from all known wild-type Aβ40 fibrils, with strong intra-strand interactions that make the N terminus associated closely with the amyloid core. The pS8-Aβ40 fibril possesses strong cross-seeding ability to wild-type Aβ40 monomers, while the propagated fibrillar structure shows higher thermodynamic stability and core rigidity compared to the fibrils formed by the self-nucleation of wild-type Aβ40. Our finding may shed light on the origin of structural polymorphisms in Aβ amyloids. The structural polymorphism in β-amyloid (Aβ) 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 Aβ (PTM-Aβ) subtypes. Although many PTM-Aβs were shown to accelerate the fibrillation process, increase neuronal cytotoxicity of aggregates, or enhance the stability of fibrils, the contribution of PTM-Aβs to structural polymorphisms and their pathological roles remains unclear. We report here the NMR-based structure for the Ser-8-phosphorylated 40-residue Aβ (pS8-Aβ40) 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-Aβ40 fibrils may potentially dominate the polymorphisms in the mixture of wild-type and phosphorylated Aβ deposits. Our results imply that Aβ subtypes with “seeding-prone” properties may influence the polymorphisms of amyloid plaques through the cross-seeding process.