A new approach to treating Alzheimer’s disease has been developed by a team of researchers at the University of Leicester, University Medical Center, Göttingen, and the medical research charity LifeArc that uses an antibody-based approach for treating Alzheimer’s disease that could also serve as a vaccine for Alzheimer’s disease.
Alzheimer’s disease is characterized by a buildup of amyloid beta (Aβ) protein plaques in the brain. Aβ protein is found in the brain of all individuals. It is highly flexible and has string-like molecules in solution that can combine to form fibers and plaques. With Alzheimer’s disease, large numbers of these string-like molecules become truncated and form plaques, which are believed to play a major role in neurodegeneration.
While treatments have been developed that focus on dissolving the protein plaques, in clinical trials none of them have had much success at reducing or reversing Alzheimer’s disease symptoms. Some of the treatments have also had negative side effects.
Rather than focusing on the Aβ protein plaques, the researchers focused on a soluble form of the Aβ peptide which is believed to be highly toxic. According to the researchers, “The Aβ peptide exists in several forms, including full-length Aβ1-42 and Aβ1-40—and the N-truncated species, pyroglutamate Aβ3-42 and Aβ4-42, which appear to play a major role in neurodegeneration.”
The researchers discovered a unique conformational epitope in the N-terminal region of Aβ, which could be targeted in active and passive immunization against Alzheimer’s disease.
The researchers had previously identified an antibody in mice (TAP01) that specifically binds to this soluble form of the peptide and neutralizes the truncated forms of the Aβ peptide, but does not bind to the normal forms of the protein or the plaques. The antibody was humanized (TAP01-04) so the immune system would accept it, and when the University of Leicester researchers looked at where the TAP01-04 was binding, they found the amyloid beta protein was folded back on itself, in a hairpin-shaped structure.
“This structure had never been seen before in amyloid beta. However, discovering such a definite structure allowed the team to engineer this region of the protein to stabilize the hairpin shape and bind to the antibody in the same way,” said Professor Mark Carr, from the Leicester Institute of Structural and Chemical Biology at the University of Leicester. “Our idea was that this engineered form of amyloid beta could potentially be used as a vaccine, to trigger someone’s immune system to make TAP01_04 type antibodies.”
The engineered amyloid beta protein was tested in mice and they found mice who received protein as a ‘vaccine’ did produce TAP01 type antibodies. The German researchers tested the humanized antibody and the amyloid beta vaccine (TAPAS) in two mouse models of Alzheimer’s disease and determined the antibody and the vaccine helped restore neuron function, increase glucose metabolism in the brain, and restore memory loss. While the researchers were not directly targeting amyloid beta plaques, there was a reduction in amyloid beta plaque formation.
”The TAP01_04 humanized antibody and the TAPAS vaccine are very different to previous antibodies or vaccines for Alzheimer’s disease that have been tested in clinical trials because they target a different form of the protein,” said Dr. Preeti Bakrania of LifeArc. “This makes them really promising as a potential treatment for the disease either as a therapeutic antibody or a vaccine. The results so far are very exciting and testament to the scientific expertise of the team. If the treatment does prove successful, it could transform the lives of many patients.”
The researchers are currently seeking a commercial partner to test the effectiveness of the vaccine and antibody in human clinical trials.
You can read more about the study in the paper – Discovery of a novel pseudo β-hairpin structure of N-truncated amyloid-β for use as a vaccine against Alzheimer’s disease – which was recently published in Molecular Psychiatry. DOI: 10.1038/s41380-021-01385-7