Structural reconstruction of individual filaments in Aβ42 fibril populations assembledin vitroreveal rare species that resembleex vivoamyloid polymorphs from human brains

Abstract

AbstractStructural polymorphism has been demonstrated for bothin vitroandex vivoamyloid 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 Aβ42amyloid fibril populations formedin vitrounder most frequently used buffer conditions. The data show sensitivity of Aβ42fibril 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 Aβ42amyloid polymorphs purified from human patient brains were discovered. These results linkin vitroexperimental approaches with structures formedin 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.