Researchers from Göttingen and Bonn have now shed light on this microscopic process. The study published in “Angewandte Chemie” might help to work out strategies for developing potential drugs. As the team of scientist including Markus Zweckstetter and Eckhard Mandelkow report, methylene blue inactivates molecular residues that promote the bonding of tau proteins.
Methylene blue is a multi-talented substance with a long history. The synthetic compound was first produced in 1876, and since then has served not only as a blue dye, but also as a medical drug – for example to treat malaria and prevent urinary tract infections. It is now also being debated as a potential treatment for Alzheimer’s disease.
Methylene blue works in many ways. With regard to Alzheimer’s, it is interesting to note that it prevents the clumping of “tau proteins”. Such aggregates are typical in numerous forms of dementia: The protein clumps accumulate in the brain cells, disrupt their function, and can even kill them.
“Tau proteins are actually extremely important, because they stabilize the transport routes inside each nerve cell,” explains Prof. Eckhard Mandelkow, who works at the German Center for Neurodegenerative Diseases (DZNE) and the caesar research center in Bonn. “However, in cases of Alzheimer’s, they stop doing their job. The transport routes inside the cells break down, and supplies essential for the survival of the cells can no longer reach their destination. In addition, the tau proteins stick together. These aggregates are also harmful and are a typical characteristic of the disease.”
Such characteristics can be reproduced in animal studies. Previously, another team of scientists led by Dr. Eva-Maria Mandelkow was able to prove that methylene blue is able to alleviate the symptoms of an illness in mice and threadworms. However, no significant data from human patients has been collected so far. Furthermore, to date it was unknown, why methylene blue had the observed effect. “Methylene blue inhibits the aggregation process,” Eckhard Mandelkow emphasizes. “But the way in which this happens was unknown until now.”The study now published in “Angewandte Chemie“ reveals the nature of this process: Markus Zweckstetter’s research group at the DZNE site in Göttingen and the Max Planck Institute for Biophysical Chemistry in Göttingen in collaboration with the Mandelkow team have been able to prove that methylene blue deactivates molecular residues which promote the bonding of tau proteins. Moreover, the researchers found indications that the substance acts as a spacer to keep the proteins apart. These findings could lead to the development of modified forms of methylene blue and new types of treatment.
This reaction is highly effective. Methylene blue specifically modifies the tau proteins at critical spots: Of the up to 441 elements which a tau protein can consist of particularly the two cysteines are modified. The elements directly modified are the so-called SH groups, molecular appendages comprising sulphur and hydrogen which are typical of cysteines. Oxygen atoms now couple with them.
“This chemical transformation prevents tau proteins from bonding together,” says Zweckstetter. “Otherwise SH groups from different proteins would react and form a so-called disulfide bridge. Now, this is no longer possible, because the reaction with methylene blue eliminates the SH groups.”
In a healthy organism, the formation of these disulfide bridges is suppressed naturally. “The cell tries to prevent harmful reactions with the help of antioxidants,” says Eckhard Mandelkow. “However, with age and in cases of neurodegenerative diseases such as Alzheimer’s, this protective system weakens allowing tau proteins to aggregate.”
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.”Original Publication
The German Center for Neurodegenerative Diseases (DZNE) investigates the causes of diseases of the nervous system and develops strategies for prevention, treatment and care. It is an institution of the Helmholtz Association of German Research Centres with sites in Berlin, Bonn, Dresden, Göttingen, Magdeburg, Munich, Rostock/Greifswald, Tübingen and Witten.
Dr. Marcus Neitzert | idw
Individual Receptors Caught at Work
19.10.2017 | Julius-Maximilians-Universität Würzburg
Rapid environmental change makes species more vulnerable to extinction
19.10.2017 | Universität Zürich
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
19.10.2017 | Materials Sciences
19.10.2017 | Materials Sciences
19.10.2017 | Physics and Astronomy