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More effective treatment of Alzheimer’s

Press release -

More effective treatment of Alzheimer’s

Researchers at Uppsala University have designed new antibodies that might provide more effective treatment methods for Alzheimer’s disease. By designing antibodies that bind even to the smaller aggregates, or clumps, of the amyloid-beta protein, it may be possible to check the progress of the disease. The results presents in Translational Neurodegeneration.

Peer-reviewed/experimental study/cells

Developing effective treatment methods for Alzheimer’s disease has proved difficult. The most effective, which have just been approved, only provide marginal effects. There are several major reasons why they are not effective, one of which is that the antibodies used do not bind to all the types of toxic clumps that cause Alzheimer’s disease.

In Alzheimer’s disease, the amyloid-beta protein begins to form clumps. This process is called aggregation, and the clumps created are called aggregates. The research group has previously shown that treatment with the peptide somatostatin causes the body to begin breaking down building blocks of the aggregate. In the new study, the researchers use an antibody that can bind to the toxic aggregates to stop them from harming cells.

The problem with the treatment methods currently tested in patient studies is that the antibodies bind much more strongly to large clumps and hardly at all to small clumps. The small clumps are just as toxic as the large ones and many think that they are actually even more dangerous since they can move more.

The purpose of the current study was to develop an antibody format that can bind to both large and small clumps of amyloid-beta. Antibodies use the avidity effect to bind strongly to their targets. This requires the binding of both arms of the antibody to the same target at the same time (see figure).

The distance between the arms of the antibody is crucial for how small an aggregate the antibody can bind to strongly. If the aggregate is smaller than the distance between the arms, they do not bind to the aggregate strongly. If it is larger, they bind to the aggregate very strongly. In the new article, the researchers have developed a new antibody format with shorter distances between the arms so that they bind to smaller aggregates. The new format also has more binding sites to make the binding extra strong.

“Thanks to the avidity effect, the new antibody format is at least 40 times stronger in binding to the clumps. The new type of antibody can also bind to small aggregates with avidity, which we have not previously seen any other antibody do. That is fantastic,” says Greta Hultqvist, Senior lecturer and Associate Professor in Protein drug design at Uppsala University who led the study.

The effects of the antibodies were also tested in a cell culture experiment, which showed that the new antibody format could save cells from death caused by amyloid-beta aggregates. Although no pre-clinical experiments were included, the team thinks their results suggest that the new antibody design could be more effective than those trialled so far.

“The focus of the study was targeting the amyloid-beta protein in Alzheimer’s disease, but the new antibody design can be general and applicable to other disease-causing clumps. From a long-term perspective, we hope that the new format can open up new avenues for the generation of future treatments, not only in Alzheimer’s disease, but also other diseases where proteins start to form aggregates, like Parkinson’s disease,” says Fadi Rofo, doctoral student in Protein drug design at Uppsala University, and first author of the study.

Rofo, F. et al (2021); Novel multivalent design of a monoclonal antibody improves binding strength to soluble aggregates of amyloid beta, Transl Neurodegener 10, 38 (2021). https://doi.org/10.1186/s40035-021-00258-x

Further information:
Greta Hultqvist, Senior lecturer and Associate Professor in Protein drug design, Uppsala University, email: greta.hultqvist@farmbio.uu.se, phone: +46-18-471 40 15, +46-70-225 35 22


More research: New method shows great potential for the treatment of Alzheimer’s disease, press release 2020, https://www.uu.se/en/press/press-release/?id=5232&typ=pm&lang=en


FACTS IN BRIEF: Amyloid-beta and aggregates in Alzheimer’s disease

Alzheimer’s disease is caused by the peptide amyloid-beta clumping in the brain. This clumping is called aggregation. Amyloid-beta not in aggregated form is present in all humans and does not cause disease, but when it starts to aggregate, that is when it becomes toxic. Initially, these aggregates are so small that they cannot be seen with a microscope. When they are this small, they can move about quite unhindered in the brain and damage neurons. If enough neurons die, you start finding it difficult to remember things.

The aggregates continue to grow and eventually become so large that you can see them with the naked eye. This is called plaque. In people who have died from Alzheimer’s disease, plaque is present in much of the brain.

In the past, it was thought that it was these plaques that were the villain, but now most researchers believe that they do not do much damage because they are large and immobile. Rather, it’s the tiny aggregates that are the most dangerous. Even these aggregates vary greatly in size and the smallest ones have been very difficult to target with various treatment methods.

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Uppsala University - quality, knowledge, and creativity since 1477

Founded in 1477, Uppsala University is the oldest university in Sweden. With more than 50,000 students and 7,500 employees in Uppsala and Visby, we are a broad university with research in social sciences, humanities, technology, natural sciences, medicine and pharmacology. Our mission is to conduct education and research of the highest quality and relevance to society on a long-term basis. Uppsala University is regularly ranked among the world’s top universities.

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