Alzheimer's disease: changing the target
A group of researchers from the University of Leicester, the University Medical Center of Göttingen and the medical research charity LifeArc have developed a new antibody and vaccine aimed not at beta-amyloid plaques, but at a soluble form of beta-amyloid, which is considered highly toxic.
Beta-amyloid in the body exists in the form of very flexible, filamentous molecules in solution that can join together to form fibers and plaques. In Alzheimer's disease, most of these filamentous molecules are shortened or "truncated", and some scientists believe that these truncated forms of beta-amyloid (pyroglutamate Aß3-42 and Aß4-42) are key to the development and progression of the disease.
In various clinical studies, none of the potential treatments that destroy amyloid plaques in the brain has shown significant success in terms of reducing the clinical symptoms of Alzheimer's disease. The authors of the study chose a different approach. They identified an antibody in mice that neutralizes truncated forms of soluble beta-amyloid, and does not bind to either normal forms of protein or plaques.
Then they adapted this antibody in such a way that the human immune system did not recognize it as a foreign agent. The research team studied how and where this "humanized" antibody TAP01_04 bound to the truncated form of beta-amyloid and found that the latter itself packed into a hairpin-shaped structure.
This beta-amyloid structure had never been observed before, and its detection allowed the group to design a hairpin-shaped protein fragment capable of binding to an antibody in the same way. The idea was that this engineered form of beta-amyloid, the TAPAS vaccine (N-Truncated Amyloid Peptide AntibodieS, antibodies to N-truncated amyloid peptide) could potentially be used as a vaccine to activate the immune system to produce TAP01_04 type antibodies.
When the researchers injected the developed fragment of beta-amyloid protein into mice, they found that the mice that received this "vaccine" produced antibodies of the TAP01 type.
The team then tested both the humanized antibody and the developed trial vaccine TAPAS against beta-amyloid on two different mouse models of Alzheimer's disease. Based on imaging techniques similar to those used to diagnose Alzheimer's disease in humans, they found that both the antibody and the vaccine helped restore neuronal function, boost glucose metabolism in the brain, regain lost memory and reduce the formation of beta-amyloid plaques.
The humanized antibody TAP01_04 and the TAPAS vaccine are very different from previous antibodies or vaccines against Alzheimer's disease that have been tested in clinical trials because they target a different form of the beta-amyloid protein. This makes them potentially promising means of treating the disease either as a therapeutic antibody or as a preventive vaccine.
According to the authors, if the results obtained are reproduced in human clinical trials, it will make it possible not only to cure Alzheimer's disease after the symptoms are detected, but also to vaccinate clinically healthy people. They are currently looking for a commercial partner to conduct clinical trials of a therapeutic antibody and vaccine.
Article by P.Bakrania et al. The discovery of a novel pseudo β-hairpin structure of N-truncated amyloid-β for use as a vaccine against Alzheimer's disease is published in the journal Molecular Psychiatry.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the University of Leicester: New approach provides potential vaccine and treatment for Alzheimer's.