New research shows chronic neurodegeneration can be prevented after traumatic brain injury

Violent blows or impacts to the head can cause traumatic brain injury (TBI), and there are currently approximately five million people in the U.S. living with chronic neurodegeneration and related disabilities as a result of TBI. In addition to cognitive and mental health disabilities, chronic neurodegeneration may also contribute to why TBI increases 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 TBI progresses to chronic neurodegeneration, there are currently no treatments that protect patients from this outcome. Now, researchers from University Hospitals (UH) and Case Western Reserve University have come one step closer to finding answers in a recent study published in Cell Reports Medicine.

“We started with the hypothesis that TBI might pathologically disrupt the balance of mitochondrial fission and fusion,” explained Preethy S. Sridharan, Ph.D., lead author of the study. “The normal homeostatic balance of mitochondrial fission and fusion is how mitochondria consistently produce enough energy for the cell, while also storing and removing damaged parts. Given the brain’s very high energy needs, this is particularly important for brain health throughout our lives.”

The process is driven by the interaction of two cellular proteins: Fis1 and Drp1. Previously, it was shown that other neurodegenerative diseases, including Alzheimer’s disease (AD) and Huntington’s disease, exhibit pathologically increased mitochondrial fission due to increased expression of Drp1. Here, the research team discovered that mitochondrial fission is also pathologically increased in TBI in mice and humans, but that it is caused by increased expression of Fis1 rather than Drp1.

They then tested whether pharmacologically reducing excessive mitochondrial fission for just two weeks after TBI, by administering a small peptide agent called P110 that blocks the interaction of Fis1 and Drp1, could halt 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.

“Brief P110 treatment during the acute period after TBI permanently normalized mitochondrial fission and prevented subsequent brain damage, including oxidative damage, blood-brain barrier impairment, axonal degeneration, and cognitive impairment, 17 months later. This is equivalent to many decades in humans,” explained Andrew A. Pieper, MD, PhD, lead author of the study and director of the Brain Health Medicines Center at the Harrington Discovery Institute at UH. “However, the same treatment administered much later had no protective effect. Thus, there is a critical window of time after TBI when this treatment may be effective.”

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

In addition to expanding their research to additional different preclinical models of TBI, the research team also plans to investigate whether the mechanism they discovered could play a role in why TBI accelerates AD. They speculate that the combination of increasing two components of the same system (increased Fis1 in TBI and increased Drp1 in AD) could produce a synergistic deleterious effect that significantly accelerates the development and severity of AD after patients experience TBI.