New study shows chronic neurodegeneration can be prevented after head trauma

Severe blows or jolts to the head can cause traumatic brain injuries (TBIs). Currently, approximately five million people in the United States suffer from chronic neurodegeneration and disorders associated with these injuries. In addition to cognitive and mental health disorders, chronic neurodegeneration may also explain why TBIs increase the risk of age-related neurodegenerative diseases, such as Alzheimer’s or Parkinson’s disease. It may also play a role in chronic traumatic encephalopathy (CTE).

However, due to the lack of understanding of why acute brain injuries turn into chronic neurodegeneration, there are currently no treatments that protect patients from this progression. Now, researchers from University Hospitals (UH) and Case Western Reserve University have moved one step closer to finding answers in a study recently published in Reports on medicine cells.

“We hypothesized that brain trauma might pathologically alter the balance between mitochondrial fission and fusion,” said Preethy S. Sridharan, Ph.D., lead author of the study. “The normal homeostatic balance of mitochondrial fission and fusion allows mitochondria to produce sufficient energy for the cell while sequestering and removing damaged parts. Given the brain’s very high energy demands, this is particularly important for brain health throughout our lives.”

The process is driven by the interaction of two cellular proteins: Fis1 and Drp1. Other neurodegenerative diseases, including Alzheimer’s disease (AD) and Huntington’s disease, have previously been shown to have pathologically elevated mitochondrial fission due to elevated Drp1 expression. Here, the research team found that mitochondrial fission is also pathologically elevated in traumatic brain injury in mice and humans, but is caused by increased expression of Fis1, rather than Drp1.

They then tested whether pharmacologically reducing excessive mitochondrial fission for just two weeks after head trauma, by administering a small peptide agent called P110 that blocks the interaction of Fis1 and Drp1, could stop this process and protect the brain. P110 was previously discovered and developed by co-senior author Xin Qi, Ph.D., the Jeanette M. and Joseph S. Silber Professor of Brain Sciences in the CWRU Department of Physiology and Biophysics and co-director of the CWRU Center for Mitochondrial Research and Therapeutics.

“A brief P110 treatment during the acute period following head trauma permanently normalized mitochondrial fission/fusion and prevented subsequent brain damage, including oxidative damage, blood-brain barrier breakdown, axonal degeneration, and cognitive impairment, 17 months later. This is equivalent to decades in people,” said Andrew A. Pieper, MD, PhD, senior author of the study and director of the Brain Health Medicines Center at the Harrington Discovery Institute at UH. “However, the same treatment given much later had no protective effect. So there is a critical time window after head trauma during which this treatment may be effective.”

The team hopes that P110 or a related compound will be clinically tested in patients with acute traumatic brain injury. “Next steps in basic science research will involve further use of this model to gain additional new insights into understanding the pathophysiology and treatment options for this important problem,” explained Dr. Qi.

In addition to extending their study to other preclinical models of traumatic brain injury, the research team also plans to determine whether the mechanism they discovered could play a role in why traumatic brain injury accelerates Alzheimer’s disease. They hypothesize that the combination of increased two components of the same system (increased Fis1 in traumatic brain injury and increased Drp1 in Alzheimer’s disease) could cause a synergistic deleterious effect that significantly accelerates the development and severity of Alzheimer’s disease after patients experience brain trauma.