After traumatic brain injury, many people experience long-term side effects. These long-term effects can last a few days or for the rest of a person’s life. Now a new study in mice by scientists at Gladstone Institutes in collaboration with Annexon Biosciences, a clinical-stage biopharmaceutical company, demonstrates there may be a potential treatment that could prevent these long-term complications.
The findings are published in the journal Science, in a paper titled, “Complement factor C1q mediates sleep spindle loss and epileptic spikes after mild brain injury.”
“No therapies currently exist to prevent the disabilities that can develop after a brain trauma,” said Jeanne Paz, PhD, associate investigator at Gladstone Institutes. “So, understanding how the traumatic brain injury affects the brain, especially in the long term, is a really important gap in research that could help develop new and better treatment options.”
“Traumatic brain injury affects millions of people every year and is a major cause of disability worldwide,” the researchers wrote. “Most of the maladaptive outcomes develop months or years later and are thought to be caused by secondary injuries that are indirect and long-term effects after the initial impact. Holden et al., found that secondary and chronic neuroinflammation and neurodegeneration are caused by the C1q molecule, a mediator of the complement pathway.”
“These injuries are frequent and can happen to anyone,” explained Paz, who is also an associate professor of neurology at University of California, San Francisco (UCSF), and a member of the Kavli Institute for Fundamental Neuroscience. “The goal of our study was to understand how the brain changes after traumatic brain injuries and how those changes can lead to chronic problems, such as the development of epilepsy, sleep disruption, and difficulty with sensory processing.”
The researchers tracked the activity of different cells and circuits in the brain of mice after brain injury.
“We collected so much data, from the time of injury and over the next several months, that it actually crashed our computers,” said Paz. “But it was important to capture all the different stages of sleep and wakefulness to get the whole picture.”
The researchers discovered that the molecule C1q was present at abnormally high levels in the thalamus for months after the initial injury, and these high levels were associated with inflammation, dysfunctional brain circuits, and the death of neurons.
“The thalamus seems particularly vulnerable, even after a mild traumatic brain injury,” added Stephanie Holden, PhD, first author of the study and former graduate student in Paz’s lab at Gladstone. “This doesn’t mean the cortex isn’t affected, but simply that it might have the necessary tools to recover over time. Our findings suggest that the higher levels of C1q in the thalamus could contribute to several long-term effects of brain injury.”
The Paz lab collaborated with Eleonora Aronica, MD, PhD, a neuropathologist at the University of Amsterdam, to validate their findings in human brain tissues obtained from autopsies. They also worked with fellow Gladstone assistant investigator Ryan Corces, PhD, and determined that C1q in the thalamus likely came from microglia, the immune cells in the brain.
“Our study answered some very big questions in the field about where and how changes are happening in the brain after a trauma, and which ones are actually important for causing deficits,” said Paz.
Paz then reached out to her collaborators at Annexon Biosciences, who produce a clinical antibody that can block the activity of the C1q molecule. Then, her team treated the mice who sustained brain injury with this antibody to see if it might have beneficial effects.
When C1q was blocked, chronic inflammation and the loss of neurons in the thalamus were prevented.
“This indicates that the C1q molecule shouldn’t be blocked at the time of injury, because it’s likely very important at this stage for protecting the brain and helping prevent cell death,” said Holden. “But at later time points, blocking C1q can actually reduce harmful inflammatory responses. It’s a way of telling the brain, ‘It’s okay, you’ve done the protective part and you can now turn off the inflammation.’”
“There is a paucity of treatments for patients who have suffered from an acute brain injury,” said Ted Yednock, PhD, executive vice president and CSO at Annexon Biosciences, and an author of the study. “This result is exciting because it suggests that we could treat patients in the hours to days after an acute injury like traumatic brain injury to protect against secondary neuronal damage and provide significant functional benefit.”
The study suggests that targeting the C1q molecule after injury could prevent some of the long-term consequences of traumatic brain injury and may pave the way for potential treatments for traumatic brain injury.
“The holy grail would be to have a treatment that could be offered to a patient after a trauma and that would prevent chronic inflammation in the brain, sleep disruption, and seizures,” Paz concluded. “Wouldn’t it be wonderful if our study helped make that a reality?”
