Analysis Reveals Detailed Structural Features of Amyloid Oligomers

They reported in the June 28, 2013, issue of the Journal of Biological Chemistry that transmission electron microscopy showed amyloid-beta42 oligomers were globular structures with diameters of about seven to eight nanometers. Circular dichroism revealed primarily beta-structures, while X-ray powder diffraction suggested a highly ordered intrasheet hydrogen-bonding network with heterogeneous intersheet packing. Residue-level mobility analysis on spin labels introduced at 14 different positions showed a structured state but with a disordered state at all labeling sites. Side chain mobility analysis suggested that structural order increased from N- to C-terminal regions. Intermolecular distance measurements at 14 residue positions suggested that C-terminal residues glycine-29 to valine-40 formed a tightly packed core with intermolecular distances in a narrow range of 1.15–1.25 nm.

The authors suggested that the significant structural and organizational differences that distinguished amyloid-beta42 globulomers from the free peptide and amyloid-plaque forms may help to explain the lack of success of experimental anti-Alzheimer's disease drugs that targeted amyloid plaques while ignoring the globulomeric form of the molecule.

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