Researchers from Aarhus University have identified a cellular defect that may influence the development of Alzheimer’s disease.
The study, published in Alzheimer’s & Dementia, reports that brain cells with a specific mutation in the SORL1 gene produce fewer and functionally impaired exosomes—tiny vesicles that mediate intercellular communication.
SORL1 mutation impairs cell communication
Inherited forms of Alzheimer’s disease have been linked to mutations in four primary genes. One of these, SORL1, encodes the SORLA protein, which is involved in directing proteins to appropriate locations within the cell. In this study, researchers examined how a mutation in SORL1 affects the release and function of exosomes.
Exosomes
Exosomes are extracellular vesicles released by cells that transport proteins, lipids, and genetic material between cells. They play a role in communication, immune responses and the removal of cellular waste.
SORLA protein
SORLA is a protein involved in transporting molecules within cells. It helps prevent the buildup of harmful proteins by directing them to be degraded. Defects in SORLA have been linked to neurodegenerative diseases.
The research team observed that where 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,” said study author Kristian Juul-Madsen, an assistant professor at Aarhus University.
Immune cell exosomes may play protective role in the brain
“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 Juul-Madsen.
The research team’s findings, which highlight how brain cells perform worse at producing exosomes when SORLA protein is defective, could have a significant impact on future research into Alzheimer’s and neurodegenerative diseases.
“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 said.
Alzheimer’s remains without a cure
Although the findings were observed in induced pluripotent stem cell (iPSC) models, the results contribute to a growing body of evidence that links altered exosome biology to the development of Alzheimer’s disease.
“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,” said Juul-Madsen.
Alzheimer’s disease is the most prevalent form of age-related dementia in Denmark, affecting an estimated 55,000 individuals. Current treatments can offer limited symptom relief, though the complexity of the disease has complicated efforts to find a cure.
Reference: Juul-Madsen K, Rudolph I-M, Gomes JP, et al. Familial Alzheimer’s disease mutation identifies novel role of SORLA in release of neurotrophic exosomes. 2025. Alzheimers & Dement. doi: 10.1002/alz.70591
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