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The structure reveals how the many single Aβ protein molecules are staggered in layers on top of each other and are arranged into so-called protofilaments. Two of these protofilaments are twinned around each other to form a fibril. If several of these fibrils become entangled, then this gives rise to the typical deposits or plaques that are detected in the brain tissues of Alzheimer's patients.
"This is a milestone on the road to a fundamental understanding of amyloid structures and the related diseases," explains Prof. Dieter Willbold, director of the Institute of Physical Biology at the Heinrich Heine University Düsseldorf and director of the Institute of Complex Systems (ICS-6) of the Forschungszentrum Jülich." The fibril structure answers many questions about the mechanism of fibril growth and identifies the role played by a whole series of familial mutations that lead to early onset of Alzheimer's disease," says Willbold.
Resolution - Angstroms - Nanometres - Team - Magnitude
The resolution of 4 angstroms, corresponding to 0.4 nanometres, achieved by the team is within the typical magnitude of atomic radii and atomic bond lengths. In contrast to previous work, the model shows for the first time the exact position and interactions of the proteins. The Aβ molecules of the entangled protofilaments are thus not at the same level, but like a zipper they are staggered by half an interval. Furthermore, the structure elucidates the location and conformation of all 42 amino acid residues of the many individual Aβ protein molecules for the first time.
This novel and detailed structure provides a new basis for understanding the structural effect of a number of genetic modifications that increase the risk of developing the disease. They stabilize the fibrils -- as can now be seen -- by changing the blueprint of the protein at defined locations. This e.g. also explains why in nature mice do not develop Alzheimer's...
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