A team of UK and German researchers developed a new way to treat Alzheimer’s disease and potentially vaccinate against it, according to a study published in Molecular Psychiatry. This work was a collaboration between researchers at the University Medical Center Göttingen, the University of Leicester, and the medical research organisation LifeArc.
Instead of focussing on the amyloid-beta protein accumulating in the plaques in the brain —the hallmark for Alzheimer’s disease—the team decided to take a different route. They developed both an antibody-based treatment and a protein-based vaccine targeting the soluble form of the protein which is highly toxic.
Amyloid beta protein exists as a soluble and highly flexible string-like protein in solution, which can bind together to form insoluble plaques. In Alzheimer’s disease, many of these soluble molecules are cut short —truncated form— and researchers think this process is critical for the development of the disease.
“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 neutralise the truncated forms of soluble amyloid-beta, but would not bind either to normal forms of the protein or to the plaques”, said Professor Thomas Bayer from the University Medical Center Göttingen.
The team adapted this antibody to ensure the patient’s body would not be recognised as foreign and attack it. Interestingly, when they used this humanised version—called TAP01_04–, they realised that the soluble amyloid protein was forced to fold back on itself when bound to the antibody.
“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 stabilise 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”, said Professor Mark Carr from the University of Leicester.
When they tested the engineered amyloid-beta protein in mice, they found that mice injected with this vaccine (called TAPAS) could produce TAP01 antibodies. In addition, both the antibody and the vaccine restored neuronal function, increased glucose metabolism in the brain, and prevented memory loss even though they weren’t directly targeting amyloid-beta plaque formation.
’The TAP01_04 humanised 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. 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”, said Dr. Bakrania from LifeArc.
“While the science is currently still at an early stage, if these results were to be replicated in human clinical trials, then it could be transformative. It opens up the possibility to not only treat Alzheimer’s once symptoms are detected, but also to potentially vaccinate against the disease before symptoms appear”, concluded Professor Carr.