A new study suggests that restoring levels of a key brain molecule called pleiotrophin could help improve brain function in Down syndrome — and possibly in other neurological diseases.

Researchers from the Salk Institute for Biological Studies and the University of Virginia (UVA) School of Medicine report that boosting pleiotrophin levels in the brain improved neural circuitry and cognitive function in adult mice modeling Down syndrome, even after brain development was complete.

The findings, published in the journal Cell Reports, provide new hope for future therapies that could one day enhance brain plasticity and cognitive function in people living with Down syndrome.

A Molecule Critical for Brain Development

Down syndrome — a genetic condition that affects roughly 1 in 640 births in the United States — is caused by an extra copy of chromosome 21. It leads to developmental delays, learning challenges, and increased risks of health issues such as heart defects and thyroid disorders.

The Salk team, led by Nicola J. Allen, PhD, set out to identify proteins that are altered in Down syndrome and discovered that pleiotrophin levels were significantly reduced in the brains of affected mice.

Pleiotrophin is a protein that plays an essential role in forming and maintaining synapses — the communication points between neurons — and in developing axons and dendrites, which are vital for brain signaling.

Restoring Brain Function in Adult Mice

To test whether restoring pleiotrophin could improve brain function, researchers used a gene therapy approach involving harmless viral vectors engineered to deliver the pleiotrophin gene directly to brain cells known as astrocytes.

Astrocytes are supportive brain cells that regulate neurotransmission and secrete molecules influencing synaptic strength and plasticity.

When pleiotrophin was delivered to astrocytes in adult Down syndrome mice, the researchers observed:

• Increased synapse density in the hippocampus — a key region for learning and memory.
• Enhanced brain plasticity, or the ability to form new neural connections.
• Improved communication within neural circuits long after development was complete.

“This study is exciting because it provides proof-of-concept that we can target astrocytes — a cell type specialized for secreting synapse-modulating molecules — to rewire the brain circuitry even in adulthood,” said Dr. Ashley N. Brandebura, PhD, lead author of the study and current neuroscientist at UVA Health.

Implications Beyond Down Syndrome

Although the work is still in the preclinical stage and has not been tested in humans, the researchers say the findings could eventually inform new treatment strategies for other neurodevelopmental and neurodegenerative diseases, including fragile X syndrome and Alzheimer’s disease.

“This idea that astrocytes can deliver molecules to induce brain plasticity has implications for many neurological disorders,” said Dr. Brandebura. “If we can figure out how to reprogram astrocytes to deliver synaptogenic molecules, we could have a significant impact on brain repair and function.”

She emphasized that while pleiotrophin may not be the only factor involved in Down syndrome–related brain circuit disruptions, it represents a promising therapeutic target that could eventually be harnessed through gene therapy or protein infusion approaches.

Next Steps

Dr. Brandebura, who completed her postdoctoral studies at Salk, is continuing this research at UVA Health’s Brain Institute, where she is part of the Department of Neuroscience and the Center for Brain Immunology and Glia (BIG Center).

The research was supported by the Chan Zuckerberg Initiative and the National Institute of Neurological Disorders and Stroke (NIH grant F32NS117776). The authors reported no financial interests in the study.

Source: University of Virginia Health – “Restoring pleiotrophin shows promise for improving brain function in Down syndrome”