Amyloid-beta (Aβ), which is formed in the brain, is the cause of Alzheimer’s dementia. Less known is a particularly aggressive variant of the protein: “Pyroglutamate-Aβ”, which clumps at an extremely high rate, is more resistant to degradation processes and is even more toxic to brain cells.Scientists from the Jülich Research Center have now been able to gain insight into the effects of subtle differences in the structure of this molecule and the effect of clumping. The results were published in the current issue of the journal Biophysical Journal.
Aβ proteins are produced by humans in their entire lifetime and are harmless as single molecules. However, if they accumulate together, they can form harmful aggregates. The majority of the therapeutic approaches to Alzheimer’s disease are therefore directed against this protein. However, there is not only one Aβ form in the body, but a whole group of slightly different variants. One of them, the so-called pyroglutamate Aβ, is particularly suspected of playing a key role in the initiation of the disease.
Pyroglutamate Aβ lack two amino acids at one end of the molecule, a third is converted from a glutamate to a pyroglutamate. Actually, these changes are rather minor for a molecule of about 40 amino acids. However, the biochemical properties change dramatically: the pyroglutamate variant clogs more than a hundred times faster to harmful aggregates than the “unabridged” form Aβ (1-42). “This points to a key role in the disease process and makes this protein form an important target for active ingredients,” says Prof. Dieter Willbold, Director at the Jülich Institute of Complex Systems.”Also for our own drug candidate developed in Jülich, which binds to this Aβ variant, among other things.” In the Alzheimer’s typical amyloid plaques in the brain, the pyroglutamate variant is found as a disproportionately frequent component: it accounts for about 20 percent of all Aβ proteins in the brain, but up to 50 percent of the protein in the deposits.
However, what is different at the molecular level when pyroglutamate-Aβ clumps is almost unknown until now.Especially the high speed of aggregate formation makes the investigation difficult.For the few suitable methods, a state would have to remain stable for some time in order to be able to analyze it at all. The Jülich team, led by first author Dr. Christina Dammers, has now for the first time established an approach that allows the protein and its rapid accelerated aggregation to be analyzed using the high-resolution NMR spectroscopy method.
As they have shown, the change in the three amino acids unexpectedly has far-reaching effects on the molecule. The orientations of the next ten amino acids to one another are also changed so that a total of about one third of the protein is affected. There was also a difference in the early stages of aggregation. “The deposits consist in the end of flat, so-called beta-sheets,” says Willbold. “For the first time, however, we have seen that these do not immediately form with pyroglutamate Aβ but form an intermediate stage with so-called helical structures.” These protein structure forms resembling an annoyed telephone cord do not occur in the other Aβ forms. The approach could be used for further experiments to obtain more accurate information for a deeper understanding of different protein forms and targeted therapeutic approaches.