Fine structure study of Aβ 1–42 fibrillogenesis with atomic force microscopy

One of the hallmarks of Alzheimer's disease is the self‐aggregation of the amyloid β peptide (Aβ) in extracellular amyloid fibrils. Among the different forms of Aβ, the 42‐residue fragment (Aβ 1–42 ) readily self‐associates and forms nucleation centers from where fibrils can quickly grow. The strong tendency of Aβ 1–42 to aggregate is one of the reasons for the scarcity of data on its fibril formation process. We have used atomic force microscopy (AFM) to visualize in liquid environment the fibrillogenesis of synthetic Aβ 1–42 on hydrophilic and hydrophobic surfaces. The results presented provide nanometric resolution of the main structures characteristic of the several steps from monomeric Aβ 1–42 to mature fibrils in vitro. Oligomeric globular aggregates of Aβ 1–42 precede the appearance of protofibrils, the first fibrillar species, although we have not obtained direct evidence of oligomer‐protofibril interconversion. The protofibril dimensions deduced from our AFM images are consistent with a model that postulates the stacking of the peptide in a hairpin conformation perpendicular to the long axis of the protofibril, forming single β‐sheets ribbon‐shaped. The most abundant form of Aβ 1–42 fibril exhibits a nodular structure with a ∼100‐nm periodicity. This length is very similar 1) to the length of protofibril bundles that are the dominant feature at earlier stages in the aggregation process, 2) to the period of helical structures that have been observed in the core of fibrils, and 3) to the distance between regularly spaced, structurally weak fibril points. Taken together, these data are consistent with the existence of a ∼100‐nm long basic protofibril unit that is a key fibril building block.