Mechanism of action of a potential drug for the treatment of Alzheimer's disease
The ability of methylene blue to prevent the formation of aggregates of tau proteins associated with Alzheimer's disease has been known before, but the mechanisms of this effect have not yet been clear. German researchers from Göttingen and Bonn managed to decipher it, which will help in developing strategies for creating new drugs for the treatment of this disease.
Methylene blue was first synthesized in 1876. Since then, it has been used not only as a dye, but also as a broad-spectrum medical drug, examples of applications of which are the treatment of malaria and the prevention of infections of the genitourinary tract, as well as antidotes for poisoning with cyanides, carbon monoxide and hydrogen sulfide.
Methylene blue exerts its effect through a variety of mechanisms. Recently, experts have been interested in the ability of this compound to prevent the formation of aggregates of tau proteins formed in the brain tissue of people with various forms of dementia. Such protein aggregates accumulate in the neurons of the brain, disrupt their functioning and can even lead to cell death.
According to one of the leaders of the study, Professor Eckhard Mandelkow, tau proteins are extremely important for stabilizing transport routes inside nerve cells. However, in diseases such as Alzheimer's disease, they lose the ability to perform their functions. Intracellular transport pathways are destroyed, and the connections necessary for the survival of nerve cells cannot reach their goal. In addition, the aggregates of tau proteins formed in this case have a toxic effect on the cells themselves.
Earlier experiments have shown that methylene blue relieves the symptoms of simulated Alzheimer's disease in mice and nematodes. However, there is no data on the effect of this compound on the condition of people with Alzheimer's disease to date; moreover, the mechanism of its action has not been known until today.
Using NMR spectroscopy, the authors demonstrated for the first time that methylene blue inactivates molecular residues – sulfur groups that ensure the bonding of tau protein molecules to each other. These observations should help in the development of modified forms of the drug and new approaches to the treatment of Alzheimer's disease.
Professor Mandelkov explains that in a healthy body, the formation of disulfide bridges between tau protein molecules is suppressed naturally with the help of antioxidants. However, with age, this protective system weakens, which increases the likelihood of the formation of aggregates of tau proteins.
He also emphasizes that, in addition to the formation of disulfide bridges, aggregates of tau proteins can be formed as a result of another, much slower process, when, at a certain spatial position relative to each other, zigzag tau protein molecules can converge and form so-called beta layers.
Experiments have shown that methylene blue and, to an even greater extent, its derivatives, known as azur A and azur B, also suppress this mechanism of formation of tau protein aggregates by blocking the corresponding regions of the protein molecule.
In addition to methylene blue, there are other compounds capable of suppressing the aggregation of tau proteins. Researchers believe that effective therapy for Alzheimer's disease may require a combination of different compounds with similar effects.
Article by Elias Akoury et al. The Mechanical Basis of Phenothiazine-Driven Inhibition of Tau Aggregation is published in the journal Angewandte Chemie International Edition.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on Helmholtz Association of German Research Centers:
Researchers decipher modus operandi of potential Alzheimer’s drug.
01.03.2013