Pathway Discovered to Treat Rare Childhood Dementia

Rare Daily Staff

A research study from the University of Sydney and UK Dementia Research Institute uncovers the mechanisms underlying Aicardi-Goutières syndrome, a rare disease that can cause childhood dementia.

The study, published in the journal Immunity, could lead to needed new therapeutic targets for the condition.

Aicardi-Goutières syndrome (AGS) is an autoinflammatory condition, and one of about 100 rare neurodegenerative genetic disorders identified as a potential cause of childhood dementia. It affects the white matter in the brain and is caused by a mutation in one or more of a small group of genes.

AGS is characterized by abnormal production of a protein called interferon-alpha, which is usually produced by the body in response to viral infections. However, where the interferon-alpha originates from and which parts of the brain it affects are not yet known. In this study, the researchers aimed to uncover how the brain responds to increased interferon-alpha in AGS, and how this leads to brain disease.

AGS is part of a larger group of disorders collectively termed ‘cerebral interferonopathies’, that all involve the chronic overproduction of a pro-inflammatory molecule, interferon-alpha. Findings from this study will also have a broader impact on our understanding of how interferon-alpha mediates disease.

“This research is promising as its focus on blood vessels,” said Markus Hofer, associate professor at the University of Sydney and co-lead of the study. “Blood vessels, unlike brain tissue, are more readily accessible to drugs. This provides a pathway to treatment.”

By comparing samples of cerebrospinal fluid from people with AGS to healthy controls, the researchers established that the brain itself is the source of harmful interferon-alpha in AGS. They then used a mouse model to replicate the over production of interferon-alpha, and revealed that the protein causes damage to the network of small blood vessels in the brain.

The team was able to show that removing interferon-alpha receptors from endothelial cells prevented the blood vessel damage in the brains of the mice, stopping the spread of the disease and prolonging the lifespan of the animals.

These results suggest that the small blood vessels in the brain play a key role in the damage seen in AGS, making them a potential target for treatment.

“By identifying the brain as the primary source of the harmful interferon-alpha and revealing its damaging effects on the brain’s small blood vessels, we have uncovered a potential target for urgently needed treatments,” said David Hunt, professor at UK Dementia Research Institute at Edinburgh and co-lead of the study. “These findings bring us closer to developing therapies that could significantly improve the quality of life and outcomes for children affected by this devastating condition.”

Photo: Markus Hofer, associate professor at the University of Sydney and co-lead of the study