A New Therapeutic Target for Traumatic Brain Injury

Katerina Akassoglou

Jae Kyu Ryu, left, and Zhaoqi Yan, right, collaborate in the Gladstone lab of Katerina Akassoglou.

The glaring absence of treatments for such a widespread condition drove a team of scientists at Gladstone Institutes to uncover, on a molecular level, how traumatic brain injuries trigger neurodegeneration—and just as importantly, how to target that process to prevent long-term damage.

“We set out to address the fundamental question of exactly what happens in the brain after injury to ignite the damaging process that destroys neurons,” says Jae Kyu Ryu, PhD, a scientific program leader in the lab of Katerina Akassoglou, PhD, at Gladstone Institutes.

Most traumatic brain injuries come as a result of falls, car crashes, or violent assaults, according to the Centers for Disease Control, but many also stem from sports accidents or certain military operations such as explosions. In each case, the external force is strong enough to move the brain within the skull, causing a significant breakdown in the blood-brain barrier and allowing blood to move in.

“We knew that a specific blood protein, fibrin, was present in the brain after traumatic brain injury, but we didn’t know until now that it plays a causative role in brain damage after injury,” says Ryu, who led the study that appears in the Journal of Neuroinflammation.

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How Blood That Leaks into the Brain Makes Immune Cells Toxic

“Our study answers, for the first time in a comprehensive way, how blood that leaks into the brain hijacks the brain’s immune system to cause toxic effects in brain diseases,” said Akassoglou, who is also director of the Center for Neurovascular Brain Immunology at Gladstone and a professor of neurology at UC San Francisco (UCSF). “Knowing how blood affects the brain could help us develop innovative treatments for neurological diseases.”

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Nature Immunology Selected Our Image For The July 2023 Volume 24 Cover

Katerina Akassoglou and colleagues provide single-cell RNA-sequencing and phosphoproteome analyses of CNS microglia and macrophages in response to blood proteins including activated complement and fibrin. Their findings point to potential therapeutic targeting of microglia activation by immune and vascular signals.

Microglial Gi-dependent dynamics regulate brain network hyperexcitability

The immunology of blood: connecting the dots at the neurovascular interface

Fibrinogen in neurological diseases: mechanisms, imaging, therapeutics