April 25, 2023
VCU-led study will examine how traumatic brain injuries impact Alzheimer’s disease development
Traumatic brain injury is a risk factor for Alzheimer’s disease later in life, though for reasons not entirely known. A VCU-led team aims to uncover the molecular processes behind this relationship.
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Virginia Commonwealth University’s School of Medicine is leading a new study to better understand how traumatic brain injuries (TBIs) influence the development of Alzheimer’s disease. Results from the preclinical research, recently awarded a $750,000 grant from the U.S. Department of Defense, could help medical experts develop therapies for preventing or treating TBI-induced dementia later in life.
The study is being led by Kirsty Dixon, Ph.D., an associate professor at the VCU School of Medicine’s Department of Surgery, in collaboration with Elliott Mufson, Ph.D., director of the Alzheimer’s disease research laboratory at Barrow Neurological Institute, and biotechnology company INmune Bio.
A TBI occurs when a person experiences a forceful blow or jolt to the head, such as from a fall, hitting an object, or being in a vehicle crash, which can disrupt brain function. Some brain injuries are mild, with symptoms only lasting a few weeks or months, while more serious injuries can result in lifelong disability or death.
There is growing evidence that moderate and severe TBIs can also increase the risk of dementia, such as Alzheimer’s disease, years after the original head injury occurred, yet the reasons behind this connection have yet to be confirmed.
“We know that traumatic brain injuries cause an inflammatory response, which can impact a person’s cognitive and motor functional abilities. We are now starting to see that this inflammatory response doesn't just have an immediate effect on the brain, but rather, if unchecked for some time, can potentially have other cognitive consequences later in life,” Dixon said. “Our research aims to shed light on the injury-induced molecular mechanisms that may be contributing to the later development of Alzheimer’s disease.”
The project will specifically focus on two proteins that play an important role in our immune system: soluble tumor necrosis factor (sTNF) and the tumor necrosis factor receptor 1 (TNFR1). When a person experiences an injury, the two proteins bind together to trigger an inflammatory response. Under normal conditions, this kind of inflammation is a critical part of the healing process. However, when a TBI occurs, sTNF and TNFR1 can go into overdrive, and the resulting neuroinflammation can ultimately cause additional damage to the brain.
Neuroinflammation is also a key contributor to the onset of Alzheimer’s disease, and Dixon believes the inflammatory response induced by sTNF and TNFR1 could be the driving force behind TBI-induced Alzheimer’s disease. Through the new study, the researchers will use mouse models to test whether this is the case.
For this research, the team will analyze mice with brain injuries and their development of Alzheimer’s disease. Some of the mice will be given a drug called XPro1595 being developed by INmune Bio that prevents sTNF from binding to TNFR1. By selectively blocking sTNF and TNFR1 activity, the drug helps control the level of neuroinflammation following a brain injury. The researchers will examine whether inhibiting the resulting neuroinflammation prevents the occurrence or reduces the severity of injury-induced Alzheimer’s disease.
Dixon and her colleagues will also study the effects of the drug on mice that carry the ApoE4 allele, a variant of a human gene that is associated with increased risk for Alzheimer's disease.
“People with the APOE4 allele have a higher likelihood of developing Alzheimer's disease later in life. This is possibly because the allele promotes inflammation in the body by controlling TNFR1 activity,” Dixon said. “As an additional element to our research, we’ll examine how sustaining a TBI while also carrying the APOE4 allele may further exacerbate this inflammatory response, and whether blocking sTNF and TNFR1 activity negates this effect.”
While this research is only in the preclinical stage, Dixon hopes this work will eventually lead to transformational care for patients suffering from a brain injury.
“An estimated 2.5 million people in the United States sustain a TBI annually,” she said. “This study is an important step toward understanding the nuances of this condition and identifying tools to prevent long-term disability.”
Dixon, who directs the Neurotrauma Repair Laboratory at VCU, leads various research projects that investigate how inflammation promotes injuries or disease. In addition to her TBI research, she also investigates models of pancreatitis, spinal cord injury and Gulf War Illness, a multi-symptom disorder commonly found among veterans of the Gulf War.
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