Research from Gladstone Institutes reveals that a blood
coagulation protein is responsible for initiating toxic
inflammation and neuron loss after a major head injury. The
findings can inform new treatment strategies for a condition that
often presents long-term health challenges.
SAN
FRANCISCO, April 19, 2024 /PRNewswire/ -- For the
roughly 1.5 million Americans per year who survive a traumatic
brain injury, health outcomes vary widely. Not only can these
injuries lead to a loss of coordination, depression, impulsivity,
and difficulty concentrating, but they come with an amplified risk
for developing dementia in the future.
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.
Ryu and others in Akassoglou's lab have long investigated how
blood that leaks into the brain triggers neurologic diseases,
essentially by hijacking the brain's immune system and setting off
a cascade of harmful, often-irreversible effects. Fibrin, a protein
that normally helps blood coagulate, is the culprit.
"Across many neurological diseases, toxic immune responses in
the brain are triggered by blood leaks and drive
neurodegeneration," says Akassoglou, a senior investigator at
Gladstone and the director of the Center for Neurovascular Brain
Immunology at Gladstone and UC San Francisco. "Neutralizing the
toxic immune responses in the brain paves the way to new therapies
for neurological diseases."
In diseases such as Alzheimer's and multiple sclerosis, abnormal
leaks in the protective blood-brain barrier allow fibrin to seep
into areas responsible for cognitive and motor functions causing
neurodegeneration. But in this case, the traumatic brain injury
itself causes the blood to leak into the brain. The new study
showed, for the first time, that fibrin is responsible for turning
good immune cells bad, causing dangerous inflammation and
unleashing toxins that kill neurons.
The Gladstone team used state-of-the-art imaging technology to
study mouse brains, as well as brains from people who experienced a
traumatic brain injury. They also produced three-dimensional
imaging of a whole intact mouse brain, showing blood-brain barrier
leaks and abundant fibrin in traumatic brain injury. In both mouse
and human brains, fibrin was present together with activated immune
cells.
"It became clear that fibrin is activating these immune cells,"
Ryu says. "We realized that we can prevent the toxic effects if we
could block fibrin, but we had to do it in a precise way."
The team leveraged genetic tools with a specific mutation in
fibrin that can block it from activating immune cells without
affecting the protein's beneficial blood-clotting abilities. This
is especially critical for traumatic brain injuries, as excessive
bleeding into the brain has been known to occur among patients who
were taking anticoagulant medications before their injury.
Akassoglou's lab previously developed a drug, a therapeutic
monoclonal antibody, that acts only on fibrin's inflammatory
properties, without adverse effects on blood coagulation. This
fibrin-targeting immunotherapy protects from multiple sclerosis and
Alzheimer's disease in mice. A humanized version of this
first-in-class fibrin immunotherapy is already in Phase 1 safety
clinical trials by Therini Bio.
"It's exciting to have a therapeutic option to neutralize blood
toxicity in neurologic diseases," Ryu says. "Future studies are
needed to test the effects of the fibrin immunotherapy in traumatic
brain injury."
"This study identifies a potential new strategy to diminish the
devastating impacts of brain injuries," says Lennart Mucke, MD, director of the
Gladstone Institute of Neurological Disease. "Brain injuries
can have profound effects on a person's cognitive abilities,
emotional health, and motor skills, touching every part of their
life. It will be interesting to explore whether blocking the
disease-promoting effects of fibrin can improve the outcome of
brain surgeries and reduce disability when implemented after
traumatic brain injuries have occurred."
About the Study
The study, "Fibrin promotes oxidative
stress and neuronal loss in traumatic brain injury via innate
immune activation," appears in the April 15,
2024, issue of Journal of Neuroinflammation. Authors
include Terry Dean, Andrew Mendiola, Zhaoqi
Yan, Rosa Meza Acevedo,
Belinda Cabriga, Katerina Akassoglou, and Jae Kyu Ryu.
The work was supported by the National Institutes of Health, the
Thrasher Research Fund Early Career Award, the National Multiple
Sclerosis Society, the Kaganov Scholarship for Excellence in
Neuroscience, the Conrad N. Hilton Foundation, the Dolby Family,
and the Simon Family Trust.
About Gladstone Institutes
Gladstone
Institutes is an independent, nonprofit life science research
organization that uses visionary science and technology to overcome
disease. Established in 1979, it is located in the epicenter of
biomedical and technological innovation, in the Mission Bay
neighborhood of San Francisco.
Gladstone has created a research model that disrupts how science is
done, funds big ideas, and attracts the brightest minds.
Media Contact
Kelly
Quigley
Gladstone Institutes
Director of Science Communications and Media Relations
kelly.quigley@gladstone.ucsf.edu
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