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Analysis Reveals Detailed Structural Features of Amyloid Oligomers

By BiotechDaily International staff writers
Posted on 15 Jul 2013
Image: Molecular structures of amyloid oligomers and amyloid fibers (Photo courtesy of the University of California, Los Angeles).
Image: Molecular structures of amyloid oligomers and amyloid fibers (Photo courtesy of the University of California, Los Angeles).
Advanced analytical analysis of amyloid-beta42 oligomers has yielded insights into the structure of these oligomers that helps to explain the mechanism behind the process of oligomerization and the reasons for their molecular toxicity.

Oligomerization of the 42 amino acid peptide amyloid-beta42 plays a key role in the pathogenesis of Alzheimer disease, but despite great academic and medical interest, the structure of these oligomers has not been well characterized.

In the current study, investigators at the University of California, Los Angeles (USA) employed several advanced analytical techniques to delve the secrets of the oligomeric (globulomeric) form of amyloid-beta42. 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.

Related Links:
University of California, Los Angeles



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