Peptide dimer structure in an Aβ(1–42) fibril visualized with cryo-EM

Significance β-Amyloid (Aβ) fibrils are formed from Aβ peptide and are a hallmark feature of Alzheimer’s disease (AD). Despite their involvement in AD, much remains unclear about the formation of these aggregates and their structures at the molecular level. We have obtained a 3D image of a fibril formed from the Aβ(1–42) peptide isoform using electron cryomicroscopy and built a partial atomic model based on these data. We show that the core of the fibril is formed by two peptide C termini, explaining why aggregation inhibitors are most potent when targeting the C terminus. Our model explains how addition of C-terminal amino acids may stabilize peptide interaction and how fibril stability is affected by mutations leading to familial AD. Alzheimer’s disease (AD) is a fatal neurodegenerative disorder in humans and the main cause of dementia in aging societies. The disease is characterized by the aberrant formation of β-amyloid (Aβ) peptide oligomers and fibrils. These structures may damage the brain and give rise to cerebral amyloid angiopathy, neuronal dysfunction, and cellular toxicity. Although the connection between AD and Aβ fibrillation is extensively documented, much is still unknown about the formation of these Aβ aggregates and their structures at the molecular level. Here, we combined electron cryomicroscopy, 3D reconstruction, and integrative structural modeling methods to determine the molecular architecture of a fibril formed by Aβ(1–42), a particularly pathogenic variant of Aβ peptide. Our model reveals that the individual layers of the Aβ fibril are formed by peptide dimers with face-to-face packing. The two peptides forming the dimer possess identical tilde-shaped conformations and interact with each other by packing of their hydrophobic C-terminal β-strands. The peptide C termini are located close to the main fibril axis, where they produce a hydrophobic core and are surrounded by the structurally more flexible and charged segments of the peptide N termini. The observed molecular architecture is compatible with the general chemical properties of Aβ peptide and provides a structural basis for various biological observations that illuminate the molecular underpinnings of AD. Moreover, the structure provides direct evidence for a steric zipper within a fibril formed by full-length Aβ peptide.