A New Approach for Potentially Treating and Vaccinating Against Alzheimer’s

LifeArc scientists, in collaboration with researchers in the UK and Germany, have developed a promising new approach to potentially treat Alzheimer’s disease – and also vaccinate against it.

Both the antibody-based treatment and the protein-based vaccine developed by the team reduced Alzheimer’s symptoms in mouse models of the disease. The research is published today in Molecular Psychiatry.

Targeting soluble protein

Alzheimer’s disease is the most common type of dementia, affecting more than half a million people in the UK. It is a brain disorder that slowly worsens – destroying memory, thinking and language skills. Sadly, there are currently no effective treatments to prevent, slow down or reverse the disease.

One of the hallmarks of Alzheimer’s disease is the build-up of abnormal structures called ‘amyloid plaques’ in the brain. The amyloid beta protein exists naturally in several different forms in the Alzheimer’s brain. One form can join together, eventually forming plaques that collect between nerve cells. But the same protein also comes in shorter or ‘truncated’ soluble forms, which some scientists now believe are key to the development and progression of the disease.

But the new antibody and vaccine developed in this study instead both target a different, soluble form of the amyloid beta protein, which may be more harmful to brain cells.

Professor Thomas Bayer, from the University Medical Center Göttingen, 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,” he explains “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.”

A novel hairpin-shaped structure

Dr Preeti Bakrania and colleagues at LifeArc generated a ‘humanised’ version of the antibody, called TAP01_04, which was less likely to trigger an immune response in people.

When the Leicester research group looked at how and where this antibody was binding to the truncated form of amyloid beta, they had a surprise. The team saw the amyloid beta protein was folded back on itself, in a distinctive hairpin-shaped structure – a structure which had never been seen before.

The discovery of this unique structure enabled the team to engineer a stable fragment of this region of the protein, which they showed formed a similar hairpin-shaped structure.

This engineered piece of amyloid beta could potentially be used as a vaccine to trigger a person’s immune system to make TAP01_04 type antibodies – which could provide them with protection against the development of Alzheimer’s disease.

And when the team tested the engineered amyloid beta protein in mice, they found mice that received this ‘vaccine’ did produce the required type of antibodies.

The potential to transform lives

The Göttingen group then tested both the ‘humanised’ antibody and the engineered amyloid beta vaccine, called TAPAS, in two different mouse models of Alzheimer’s disease.

Based on similar imaging techniques to those used to diagnose Alzheimer’s in humans, they found that both the antibody and the vaccine helped to restore nerve cell function, increase glucose metabolism in the brain, restore memory loss and – even though they weren’t directly targeted – reduce 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 amyloid beta protein,” explains Preeti. “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.”

Professor Mark Carr, from the Leicester Institute of Structural and Chemical Biology at the University of Leicester 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.

Reference: Bakrania P, Hall G, Bouter Y, et al. Discovery of a novel pseudo β-hairpin structure of N-truncated amyloid-β for use as a vaccine against Alzheimer’s disease. Mol Psyc. 2021. doi: 10.1038/s41380-021-01385-7.

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