Researchers discover cell defect linked to the development of Alzheimer’s

They’re tiny particles – with potentially huge human consequences. Researchers from Aarhus University have identified a defect in the production of so-called exosomes in cells, associated with a mutation seen in dementia patients. This could lead to a better understanding of the development – and perhaps even a treatment – of Alzheimer’s.

Exosomes are the epitome of microscopic. So small that just the tip of a grain of rice equals millions of them. Nevertheless, new research from the Department of Biomedicine at Aarhus University shows that they may play a key role in the development of Alzheimer’s. Assistant Professor Kristian Juul-Madsen is one of the researchers behind a new study recently published in the scientific journal Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

“Exosomes are used to communicate with and activate surrounding cells, and we have now identified a defect in both the production and the quality of exosomes in cells that we know are predisposed to Alzheimer’s.”

To date, four main genes have been identified that can be linked to the inherited form Alzheimer’s. And to understand the new research findings, we need to dive a bit into the technical explanations. One of these four genes is called Sorl1. This gene encodes the protein SORLA. And when the SORLA-protein mutates, there is a risk of developing Alzheimer’s. What Kristian Juul-Madsen and his research colleagues have now discovered is that if the SORLA-protein is defective, the brain cells become significantly worse at producing exosomes.

“We found that cells with this mutation produced 30% fewer exosomes, and those that were produced were significantly worse at stimulating the growth and maturation of surrounding cells – in fact, up to 50% less effective than in cells where the SORLA-protein is not mutated.”

And this could be crucial for future Alzheimer’s research, he says.

“It tells us that exosomes produced particularly by the brain’s immune cells play an important role in maintaining brain health – and that mutations leading to fewer and poorer quality exosomes are associated with increased risk of Alzheimer’s.”

Kristian Juul-Madsen hopes that the research findings may eventually lead to improved treatment of Alzheimer’s.

“The potential is very clear. We now have the opportunity to investigate new treatments for Alzheimer’s – either by stimulating the function of SORLA so that the cells produce more and better exosomes, or by targeting other known receptors that can enhance exosome production.”

Alzheimer’s is the most common form of age-related dementia in Denmark. It is estimated that around 55,000 Danes are affected, and there is currently no treatment for the disease.

Behind the research – more information 

• Study type: Basic research, primarily based on the use of iPSCs (induced pluripotent stem cells). We generate new stem cells that contain the mutation we want to study and compare them to cells without this disease-associated mutation. In addition, the study relies on extensive "omics" analyses, where we examined globally both the protein and RNA content of exosomes.
• Collaborators: The study was carried out as an LF Postdoc project. I therefore worked in Thomas Willnow’s laboratory at the Max Delbrück Center for Molecular Medicine in Berlin and in his laboratory at the Department of Biomedicine at Aarhus University.
• External funding: The study was primarily supported by an LF postdoctoral grant from the Lundbeck Foundation (R380-2021-1326) awarded to Kristian Juul-Madsen, and by a Laureate grant from the Novo Nordisk Foundation (NNF18OC0033928) and a research grant from the Alzheimer Forschung Initiative (18003) awarded to Prof. Thomas Willnow.
• Potential conflicts of interest: None.
• Information on deviations from the principle that research results must be based on a peer-reviewed article published in a scientific journal: No deviations.
• Read more in the scientific paper: https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.70591

Contact:

Assistant Professor, Kristian Juul-Madsen
Department of Biomedicine, Health, Aarhus University
Mail:juul-madsen@biomed.au.dk
Phone: +4561285520