Amyloid plaques are one of the hallmarks of Alzheimer’s disease. Years of research has been done to better understand these plaques and the amyloid beta protein that builds up to create them. A new study, however, has focused on a different form of amyloid beta protein that scientists think may play a role in the progression and development of the disease. This work may lead to a vaccine for Alzheimer’s.
A team of researchers from University of Leicester, the University Medical Center Göttingen, and the medical research charity LifeArc has identified an antibody that neutralizes a different soluble form of amyloid beta protein. While one form of this protein binds together to form plaques, other proteins can become shortened or truncated. Scientists believe this second form may be more harmful to brain cells. When the team used the antibody they’d identified and a protein-based vaccine to target this form of the protein in mice, Alzheimer’s symptoms were reduced. The promising findings were published in the journal Molecular Psychiatry.
Professor Thomas Bayer, team member from the University Medical Center Göttingen, explains, “In clinical trials, none of the potential treatments which dissolve amyloid plaques in the brain have shown much success in terms of reducing Alzheimer’s symptoms. Some have even shown negative side effects. So, we decided on a different approach. We identified an antibody in mice that would neutralize the truncated forms of soluble amyloid beta, but would not bind either to normal forms of the protein or to the plaques.”
To test this antibody, the researchers made a humanized version of it called TAP01_04. When they studied how it was binding to the truncated form of amyloid beta, they saw that the protein was folded back on itself in a hairpin-shaped structure. This was something that had not been seen before.
Professor Mark Carr, researcher from the Leicester Institute of Structural and Chemical Biology at the University of Leicester, says, “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. 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.”
When the engineered amyloid beta protein was administered to mice as a vaccine called TAPAS, the animals that received it did produce these antibodies.
Additionally, when the humanized antibody and the vaccine were tested in two different mouse models, both were found to restore neuron function, increase glucose metabolism in the brain, restore memory loss, and reduce amyloid beta plaque formation, even though they were not directly targeting these formations.
Dr. Preeti Bakrania, lead author and team member from LifeArc, says, “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 amyloid beta protein. The results so far are very exciting and testament to the scientific expertise of the team. If this new approach proves successful, it could transform the lives of many patients.”
To move their work forward, the researchers are looking for a commercial partner to take the antibody treatment and vaccine into clinical trials.