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A new approach that could potentially treat Alzheimer’s disease and vaccinate against it has been developed by scientists at the University of Leicester.
The study developed by the team, which suggests both an antibody-based treatment and a protein-based vaccine, has reduced the symptoms of Alzheimer’s in mouse models of the disease.
Alzheimer’s disease happens when amyloid-beta protein clumps together to form plaques that collect between neurons and disrupt the function of the brain.
The amyloid beta-protein naturally exists in the body as highly flexible, string-like molecules in solution, which can join together to form fibres and plaques between nerve cells.
When a person has Alzheimer’s, a high proportion of these molecules become shortened, and some scientists now think these forms are key to the development and progression of the disease.
Instead of focusing on the amyloid-beta protein, the study has developed a treatment and vaccine that target a different form of the protein, which is thought to be highly toxic.
These treatments have been found to reduce the symptoms of Alzheimer’s in tests on the mouse models – which shows promising signs that could lead to human trials in the future.
The study is a collaboration between researchers at the University of Leicester, the University Medical Centre Gottingen, and the medical research charity LifeArc.
Professor Thomas Bayer, from the University Medical Centre Gottingen, said: “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.”
This antibody was adapted by Dr Preeti Bakrania and colleagues from LifeArc so a human immune system would not recognise it as foreign and would accept it.
Leicester researchers were surprised when they found how and where this humanised antibody, called TAP01_04, was binding to the shortened form of amyloid beta.
They saw the amyloid beta protein was folded back on itself, in a hairpin-shaped structure.
Professor Mark Carr, from the Leicester Institute of Structural and Chemical Biology at the University of Leicester, explained: “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.”
When the engineered amyloid-beta protein was tested in mice, they found the animals that received this “vaccine” did produce TAP01 type antibodies.
The antibody and the engineered amyloid-beta vaccine, called TAPAS, were then tested in two different mouse models of Alzheimer’s disease.
Based on imaging techniques similar to those used to diagnose Alzheimer’s in humans, researchers found that both the antibody and the vaccine helped to restore neuron function.
The treatment also helped to increase glucose metabolism in the brain, restore memory loss, and while they were not directly targeted, they even reduced amyloid-beta plaque formation, according to the study.
LifeArc’s Dr. Bakrania said: “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.
“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.”
Prof Carr added: “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.”
The researchers are now looking to find a commercial partner to take the therapeutic antibody and the vaccine through clinical trials.
The findings are published in Molecular Psychiatry.
