Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of amyloid plaques in the brain. This amyloid primarily contains amyloid-β (Aβ), a 39- to 43-aa peptide derived from the proteolytic cleavage of the endogenous amyloid precursor protein. The 42-residue-length Aβ peptide (Aβ 1–42 ), the most abundant Aβ peptide found in plaques, has a much greater propensity to self-aggregate into fibrils than the other peptides and is believed to be more pathogenic. Synthetic human Aβ 1–42 peptides self-aggregate into stable but poorly-ordered helical filaments. We determined their structure to ≈10-Å resolution by using cryoEM and the iterative real-space reconstruction method. This structure reveals 2 protofilaments winding around a hollow core. Previous hairpin-like NMR models for Aβ 17–42 fit well in the cryoEM density map and reveal that the juxtaposed protofilaments are joined via the N terminus of the peptide from 1 protofilament connecting to the loop region of the peptide in the opposite protofilament. This model of mature Aβ 1–42 fibrils is markedly different from previous cryoEM models of Aβ 1–40 fibrils. In our model, the C terminus of Aβ forms the inside wall of the hollow core, which is supported by partial proteolysis analysis.

Zhang, R., Hu, X., Khant, H., Ludtke, S. J., Chiu, W., Schmid, M. F., Frieden, C., & Lee, J.-M. (2009). Interprotofilament interactions between Alzheimer’s Aβ 1–42 peptides in amyloid fibrils revealed by cryoEM. Proceedings of the National Academy of Sciences, 106(12), 4653–4658.