Amyloid β‑Protein Assembly and Alzheimer’s Disease: Dodecamers of Aβ42, but Not of Aβ40, Seed Fibril Formation

• Published in: Journal of the American Chemical Society 2016-02, Vol.138 (6), p.1772-1775
• Main Authors: Economou, Nicholas J, Giammona, Maxwell J, Do, Thanh D, Zheng, Xueyun, Teplow, David B, Buratto, Steven K, Bowers, Michael T
• Format: Article
• Language: English
• Subjects: Alzheimer disease; Alzheimer Disease - metabolism; amyloid; Amyloid beta-Peptides - metabolism; atomic force microscopy; Biopolymers - metabolism; etiology; Humans; image analysis; Microscopy, Atomic Force; solubilization
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.5b11913

Evidence suggests that oligomers of the 42-residue form of the amyloid β-protein (Aβ), Aβ42, play a critical role in the etiology of Alzheimer’s disease (AD). Here we use high resolution atomic force microscopy to directly image populations of small oligomers of Aβ42 that occur at the earliest stages of aggregation. We observe features that can be attributed to a monomer and to relatively small oligomers, including dimers, hexamers, and dodecamers. We discovered that Aβ42 hexamers and dodecamers quickly become the dominant oligomers after peptide solubilization, even at low (1 μM) concentrations and short (5 min) incubation times. Soon after (≥10 min), dodecamers are observed to seed the formation of extended, linear preprotofibrillar β-sheet structures. The preprotofibrils are a single Aβ42 layer in height and can extend several hundred nanometers in length. To our knowledge this is the first report of structures of this type. In each instance the preprotofibril is associated off center with a single layer of a dodecamer. Protofibril formation continues at longer times, but is accompanied by the formation of large, globular aggregates. Aβ40, by contrast, does not significantly form the hexamer or dodecamer but instead produces a mixture of smaller oligomers. These species lead to the formation of a branched chain-like network rather than discrete structures.