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Mild traumatic brain injury (TBI) could reactivate latent herpes simplex virus type 1 (HSV-1) in the brain, contributing to neurodegeneration and Alzheimer’s disease (AD) pathology, according to a groundbreaking study.
The research, published online on January 7 in Science Signaling, utilized a three-dimensional (3D) human brain tissue model to explore the link between TBI and HSV-1 reactivation. The findings revealed that mechanical jolts, akin to concussions, could trigger quiescent HSV-1, leading to hallmark signs of AD, including neuroinflammation, amyloid beta production, phosphorylated tau (p-tau), and gliosis. Repeated head injuries exacerbated these effects.
“This opens the question as to whether antiviral drugs or anti-inflammatory agents might be useful as early preventive treatments after head trauma to stop HSV-1 activation in its tracks and lower the risk of Alzheimer’s disease,” said lead investigator Dana Cairns, PhD, from the Department of Biomedical Engineering at Tufts University in Medford, Massachusetts.
HSV-1 and Alzheimer’s Disease Risk
TBI is a significant risk factor for AD, though the exact pathways linking the two remain elusive. HSV-1 is found in over 80% of people and can lie dormant in brain cells. Prior studies suggest that HSV-1 in the brain, particularly in individuals carrying the APOE-ε4 gene variant, significantly increases the risk of developing AD.
Using a donut-shaped, spongy 3D brain tissue model composed of silk protein and collagen infused with neural stem cells, researchers simulated concussion-like blows to study their effects. In latently HSV-1-infected tissue, the mechanical trauma reactivated the virus, initiating AD-like changes, including amyloid beta and p-tau accumulation and neuroinflammation. These effects were absent in non-infected tissue.
“Our data suggest that HSV-1 reactivation is pivotal in increasing the risk of AD,” the researchers wrote. They propose that inflammation from brain injury might trigger the reactivation of HSV-1, kickstarting neurodegeneration.
Potential Interventions and Future Directions
The study highlights the need for further exploration of post-injury treatments, such as antiviral and anti-inflammatory drugs, to prevent HSV-1 reactivation and reduce the risk of dementia.
However, external experts emphasized caution in interpreting the findings.
Tara Spires-Jones, PhD, of the British Neuroscience Association, noted limitations, including the artificial conditions of the experiments and the small number of replicates. “The observed changes do not perfectly mimic the pathology seen in human Alzheimer’s disease,” she said.
Robert Howard, MD, from University College London, pointed out that while the study suggests a possible mechanism linking TBI, HSV-1, and dementia, it does not prove causation. “Avoidance of brain injuries remains a crucial preventive strategy for dementia,” he added.
Jennifer Pocock, PhD, from UCL Queen Square Institute of Neurology, highlighted the need to examine the role of microglia, immune cells in the brain that are activated by TBI. She warned that the study’s exclusion of microglia might limit its applicability to real-world conditions.
Funding and Disclosures
The study was funded by the US Army Research Office and the Department of Defense. The authors declared no conflicts of interest. External experts Spires-Jones and Howard also reported no relevant disclosures. Pocock disclosed research funding from AstraZeneca and Daiichi Sankyo.
This research represents a significant step in understanding the potential role of HSV-1 in TBI-related neurodegeneration. However, further studies in more complex biological systems and larger sample sizes are needed to validate these findings and assess their implications for preventive treatments.
