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
How Neural Circuits Implement Natural Vision
24.05.2016 | Albert-Ludwigs-Universität Freiburg im Breisgau
Epigenetic Modification Increases Susceptibility to Obesity and Predicts Fatty Liver Later in Life
23.05.2016 | Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke
In the Beyond EUV project, the Fraunhofer Institutes for Laser Technology ILT in Aachen and for Applied Optics and Precision Engineering IOF in Jena are developing key technologies for the manufacture of a new generation of microchips using EUV radiation at a wavelength of 6.7 nm. The resulting structures are barely thicker than single atoms, and they make it possible to produce extremely integrated circuits for such items as wearables or mind-controlled prosthetic limbs.
In 1965 Gordon Moore formulated the law that came to be named after him, which states that the complexity of integrated circuits doubles every one to two...
Characterization of high-quality material reveals important details relevant to next generation nanoelectronic devices
Quantum mechanics is the field of physics governing the behavior of things on atomic scales, where things work very differently from our everyday world.
When current comes in discrete packages: Viennese scientists unravel the quantum properties of the carbon material graphene
In 2010 the Nobel Prize in physics was awarded for the discovery of the exceptional material graphene, which consists of a single layer of carbon atoms...
The trend-forward world of display technology relies on innovative materials and novel approaches to steadily advance the visual experience, for example through higher pixel densities, better contrast, larger formats or user-friendler design. Fraunhofer ISC’s newly developed materials for optics and electronics now broaden the application potential of next generation displays. Learn about lower cost-effective wet-chemical printing procedures and the new materials at the Fraunhofer ISC booth # 1021 in North Hall D during the SID International Symposium on Information Display held from 22 to 27 May 2016 at San Francisco’s Moscone Center.
Staphylococcus aureus usually is a formidable bacterial pathogen. Sometimes, however, weakened forms are found in the blood of patients. Researchers of the University of Würzburg have now identified one mutation responsible for that phenomenon.
Staphylococcus aureus is a bacterium that is frequently found on the human skin and in the nose where it usually behaves inconspicuously. However, once inside...
24.05.2016 | Event News
20.05.2016 | Event News
19.05.2016 | Event News
24.05.2016 | Physics and Astronomy
24.05.2016 | Earth Sciences
24.05.2016 | Trade Fair News