New study shows that chronic neurodegeneration can be prevented after traumatic brain injury

CLEVELAND – Violent blows or jolts to the head can cause traumatic brain injury (TBI), and there are currently about five million people in the U.S. living with chronic neurodegeneration and related impairments due to TBI. In addition to cognitive and mental health impairment, 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 could also play a role in chronic traumatic encephalopathy (CTE).

Due to the lack of understanding of why acute TBI transitions into chronic neurodegeneration, however, there are currently no treatments that protect patients from this outcome. Now, University Hospitals (UH) and Case Western Reserve University researchers have moved a step closer to finding answers in a study recently published in Cell Reports Medicine.  

“We started with the hypothesis that TBI might pathologically impair the balance of mitochondrial fission and fusion,” explained Preethy S. Sridharan, PhD, 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 sequestering and disposing damaged parts. Given the very high energy demands of the brain, this is particularly important for brain health across our lifespan.”

The process is governed by the interaction of two cellular proteins: Fis1 and Drp1. It was previously shown that other neurodegenerative diseases, including Alzheimer's disease (AD) and Huntington's disease, display pathologically elevated mitochondrial fission due to elevated expression of Drp1. Here, the research team discovered that mitochondrial fission is pathologically elevated in mouse and human TBI as well, but that it is caused by increased expression of Fis1, rather than Drp1. 

They next tested whether pharmacologically reducing excessive mitochondrial fission for only two weeks after TBI, by administering a small peptide agent named P110 that blocks the interaction of Fis1 and Drp1, might halt this process and protect the brain. P110 was previously discovered and developed by co-senior author, Xin Qi, PhD, 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 time period after TBI permanently normalized mitochondrial fission / fusion and prevented subsequent harm to the brain, including oxidative damage, blood-brain barrier deterioration, axonal degeneration, and cognitive impairment, 17 months later. This is equivalent to many decades in people,” explained Andrew A. Pieper, MD, PhD, senior author of the study and Director of the Brain Health Medicines Center of the Harrington Discovery Institute at UH. “The same treatment administered much later, however, had no protective effect. Thus, there is a critical time window after TBI wherein this treatment can be effective.”

Dr. Pieper also holds the Morley-Mather Chair in Neuropsychiatry at UH and the CWRU Rebecca E. Barchas, MD, DLFAPA, University Professorship in Translational Psychiatry. He additionally serves as Psychiatrist and Investigator in the Louis Stokes VA Geriatric Research Education and Clinical Center (GRECC).

The team hopes that P110 or a related compound will be tested clinically in acute TBI patients. “Next steps in the basic science research, on the other hand, involve further utilization of this model to yield additional new insights into understanding the pathophysiology and treatment opportunities for this important problem,” explained Dr. Qi.

In addition to extending their investigation 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 cause a synergistic deleterious effect that significantly advances the development and severity of AD after patients have experienced a TBI.

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This study was supported by The Valour Foundation.

Sridharan, Preethy S. et al. “Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury.” Cell Reports Medicine. DOI: 10.1016/j.xcrm.2024.101715

About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of more than 20 hospitals (including 5 joint ventures), more than 50 health centers and outpatient facilities, and over 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship quaternary care, academic medical center, University Hospitals Cleveland Medical Center, is affiliated with Case Western Reserve University School of Medicine, NEOMED, Oxford University, Technion Israel Institute of Technology, and National Taiwan University College of Medicine. The main campus also includes the UH Rainbow Babies & Children's Hospital, ranked among the top children’s hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, with more than 3,400 active clinical trials and research studies underway. UH Cleveland Medical Center is perennially among the highest performers in national and international ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report and UK Brand Finance. UH is also home to 19 Clinical Care Delivery and Research Institutes. UH is one of the largest employers in Northeast Ohio with more than 30,000 employees. Follow UH on LinkedIn, Facebook and Twitter. For more information, visit UHhospitals.org.

Case Western Reserve University is one of the country's leading private research institutions. Located in Cleveland, we offer a unique combination of forward-thinking educational opportunities in an inspiring cultural setting. Our leading-edge faculty engage in teaching and research in a collaborative, hands-on environment. Our nationally recognized programs include arts and sciences, dental medicine, engineering, law, management, medicine, nursing and social work. About 6,200 undergraduate and 6,100 graduate students comprise our student body. Visit case.edu to see how Case Western Reserve thinks beyond the possible.