Amyloid structure I
Abstract
Amyloid-β (Aβ) fibrils can adopt distinct structural polymorphs that may determine their biological propagation and neuropathological effects. We have isolated Aβ fibril preparations displaying homogenous structures.
We will use cryogenic electron microscopy to determine the structures of these isolated fibrils and establish whether their biological differences correspond to distinct Aβ folds, protofilament interfaces, helical symmetries, or fibril-bundling states. Substantial computational resources are required for motion correction, contrast-transfer-function estimation, automated fibril picking, two-dimensional classification, helical reconstruction, three-dimensional classification, structural refinement, and atomic model building. Comparative analysis of multiple structural classes will allow us to resolve sample heterogeneity and distinguish genuine fibril polymorphs from differences in filament association. The resulting structures will provide a molecular basis for understanding how Aβ strain architecture influences seeding and pathology.
