New research in mice highlights disease-modifying molecules produced by astrocytes in Rett, fragile X and Down syndromes

New research in mice highlights disease-modifying molecules produced by astrocytes in Rett, fragile X and Down syndromes

Neurons often get most of the credit for keeping our brains sharp and functional, as well as most of the blame when it comes to brain disease. But star-shaped cells called astrocytes, another cell abundant in the human brain, may bear the brunt of responsibility for exacerbating symptoms of certain neurodevelopmental disorders. Scientists at the Salk Institute have now identified a molecule produced by astrocytes that interferes with the normal development of neurons in Rett, Fragile X and Down syndromes.

As the team reports in Natural neuroscience on August 30, 2022, blocking the molecule reduces signs of disease in the brains of mice.

“These findings are part of a new push to examine how all brain cells, not just neurons, interact in neurodevelopmental disorders,” says Associate Professor Nicola Allen, who led the new study. “This opens the door to potential therapies to treat these disorders by targeting astrocytes. »

In recent years, scientists have discovered that astrocytes play a key role in brain development and disease. Isolated neurons, for example, do not form connections and only communicate if astrocytes are present. If astrocytes affected by disease are mixed with healthy neurons, the neurons begin to show signs of disease. Similarly, if neurons affected by neurodevelopmental disorders are exposed to healthy astrocytes, their function improves.

However, researchers have not been able to determine which molecules in astrocytes are responsible.

In the new study, Allen and his colleagues isolated astrocytes and neurons from the developing brain of mice with genetic mutations causing Rett, Fragile X or Down syndrome or from healthy animals. Next, they determined the levels of 1,235 different proteins produced by each set of astrocytes. They found hundreds of proteins present at higher or lower levels in each disease, with 120 proteins in common across the three diseases – 88 at higher than normal levels and 32 at lower than normal levels.

“From a basic science perspective, it is fascinating that there are so many observed changes in astrocyte protein secretion in these genetic disorders – and more importantly, that so many of these changes overlap between the disorders,” says Alison Caldwell, first author of the paper study and former graduate student in Allen’s lab. “To me, this highlights the importance of astrocytes for normal neuronal development. »

One molecule caught the attention of scientists. They knew that insulin-like growth factor (IGF) could sometimes reduce disease symptoms in mice with neurodevelopmental disorders. Researchers had long assumed that the treatment worked because the diseased neurons were not producing enough IGF. But they found a different explanation: astrocytes affected by Rett, fragile X or Down syndrome produce high levels of Igfbp2, a protein that blocks IGF.

“It turns out that neurons make a lot of IGF, but it can’t get to where it needs to be because these molecules made by astrocytes interfere with it,” says Allen.

The group went on to show that excess Igfbp2 produced by astrocytes is responsible for slowing neuron growth and that blocking Igfbp2 produced by Rett syndrome astrocytes improved neuron growth. Additionally, when mice with Rett syndrome were treated with Igfbp2-blocking antibodies, signs of disease in the brain were reduced.

“We still have a long way to go to get a therapy based on this for humans, but we think it shows promise,” Allen says. “Rather than giving an IGF treatment that has actions throughout the body, it makes sense to target Igfbp2 in the brain, where we want the IGF to act. »

Allen’s lab group is planning follow-up studies on other proteins they have identified in diseased astrocytes, as well as future experiments to better understand Igfbp2.

Other authors included Laura Sancho, James Deng, Alexandra Bosworth, Audrey Miglietta, Jolene Diedrich and Salk’s Maxim Shokhirev.

The work was supported in part by Autism Speaks (Dennis Weatherstone Predoctoral Fellowship), the Chapman Foundation, the National Institute of Child Health and Human Development (F30HD106699), the Chan Zuckerberg Initiative, the Hearst Foundation, and the Pew Foundation.

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