Structural reconstruction of individual filaments in Abeta42 fibril populations assembled in vitro reveal rare species that resemble ex vivo amyloid polymorphs from human brains
Structural polymorphism has been demonstrated for both in vitro and ex vivo amyloid fibrils associated with disease. The manner in which different filament structures are assembled from common building blocks remains unclear but the assembly environment is likely to be a key determinant. To address this, three-dimensional reconstruction of individual filament structures was conducted from atomic force microscopy images to map the structural polymorphism landscape of A{beta}42 amyloid fibril populations formed in vitro under most frequently used buffer conditions. The data show sensitivity of A{beta}42 fibril polymorphism to the assembly environment in both the magnitude of heterogeneity and the types of filament species formed. However, some conserved fibril polymorphs were observed across the experimental conditions. Excitingly, by matching individual filament structures to cryo-electron microscopy derived structural data, rare species in these heterogeneous population clouds that show remarkable similarity to A{beta}42 amyloid polymorphs purified from human patient brains were discovered. These results link in vitro experimental approaches with structures formed in vivo, and highlight the polymorph distribution, and the type and magnitude of structural variations within these heterogeneous molecular distributions as important factors in amyloid biology.