Defective exosome production linked to higher risk of Alzheimer’s disease

Scientists at Aarhus University have discovered that a mutation in the Sorl1 gene reduces both the number and quality of exosomes produced by brain cells, impairing their ability to support surrounding cells and heightening susceptibility to Alzheimer’s

A research team at Aarhus University, Denmark, has reported that a defect in the production of exosomes – the tiny particles used by cells to communicate – is associated with a mutation known to increase the risk of dementia. The discovery has provided fresh insight into the development of Alzheimer’s disease.

Exosomes are microscopic vesicles, so small that millions of them would fit on a grain of rice. Despite their size, they appear to play a central role in maintaining brain health. A study conducted at the Department of Biomedicine at Aarhus University has revealed that a mutation in the Sorl1 gene, which encodes the protein SORLA, significantly impairs exosome production.

“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,” said Assistant Professor Kristian Juul-Madsen, one of the authors of the study.

Four main genes have so far been linked to inherited forms of Alzheimer’s disease. Mutations in Sorl1 are known to raise the risk, and the Aarhus team has shown that defects in the protein it encodes reduce the brain’s ability to generate functional exosomes.

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“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,” said Juul-Madsen.

The findings suggest that the brain’s immune cells depend on exosomes to maintain neurological function, and that reduced quantity and quality of these vesicles correlates with heightened Alzheimer’s risk.

“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,” Juul-Madsen added.

The team expressed hope that the discovery could inform therapeutic development.

“The potential is very clear. We now have the opportunity to investigate novel 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,” said Juul-Madsen.

The study was conducted as basic research, primarily using induced pluripotent stem cells (iPSCs) generated to contain the disease-associated mutation for comparison with healthy cells. The researchers also carried out extensive omics analyses to characterise both the protein and RNA content of exosomes.

For further reading please visit: 10.1002/70591