Beta sheets also important
Zweckstetter stresses that along with the disulfide bridges, another mechanism is important for the clumping of tau proteins. "Tau proteins aggregate particularly quickly when disulfide bonds form. These work like a trigger. However, tau proteins can also aggregate without these bridges, albeit more slowly."
This is due to the structure of the molecule, the backbone of which can fold like an accordion in some places. Such regions can pile up to "beta sheets" when two proteins come together closely enough and in the appropriate orientation. "Our experiments also show a distinct effect of methylene blue on the regions that want to form these beta sheets." Thus, methylene blue, particularly its derivatives "Azure A" and "Azure B", which are expected to be predominantly present in the body, also appear to inhibit the aggregation of beta sheets. "Steric hindrance occurs," Zweckstetter guesses. "When an inhibitor attaches to a beta sheet region of the tau protein, no other tau molecule can lock on."
There are other substances besides methylene blue that can suppress the aggregation of tau proteins. Some of them focus explicitly on preventing the build-up of beta sheets. The researchers believe that an effective treatment could ultimately require a combination of various substances: "Certainly, one conclusion of our study is that there are different ways to disrupt the pathogenic aggregation of tau proteins."
|Contact: Dirk Frger|
Helmholtz Association of German Research Centres