Traumatic brain injury can reactivate herpesvirus and cause neurodegeneration

Mild traumatic brain injury (TBI) may reactivate latent herpes simplex virus type 1 (HSV-1) in the brain, contributing to neurodegeneration and progression of Alzheimer's disease (AD) pathology. A new study suggests that.

Using a three-dimensional (3D) human brain tissue model, researchers showed that quiescent HSV-1 was reactivated by a mechanical shock that mimicked concussion, leading to neuroinflammation and amyloid-β and phosphorylated tau (p -tau) and gliosis – a phenotype exacerbated by repeated head trauma.

“This raises the question of whether antiviral or anti-inflammatory drugs may be useful as early preventive treatments after head trauma to halt HSV-1 activation and reduce the risk of Alzheimer's disease. ,” said lead researcher Dr. Dana Cairns. Researchers from the Tufts University School of Biomedical Engineering in Medford, Massachusetts, said in a statement.

But outside experts urged caution in drawing firm conclusions, pending further research.

The research is Published online In the diary of January 7th science signaling.

Is HSV-1 a major risk factor for AD?

Traumatic brain injury is a major risk factor for Alzheimer's disease and dementia, but the pathways in the brain that lead from TBI to dementia are unknown.

HSV-1 is present in more than 80% of people. Varicella-zoster virus (VZV) is found in about 95% of cases. Both viruses are known to invade the brain and lodge in neurons and glial cells. Previous evidence indicates that HSV-1 is present in the human brain. APOE-ε4 Carriers pose a strong risk of Alzheimer's disease.

Several years ago, a research team created 3D models of human brain tissue to study the link between traumatic brain injury, viruses, and dementia. The model is 6 mm wide, donut-shaped, and made of a spongy material of silk protein and collagen saturated with neural stem cells. The cells mature into neurons, which communicate with each other and form networks that mimic the brain environment.

In a previous study using a model of static HSV-1 infection, Cairns et al. found that subsequent exposure to VZV triggered an inflammatory state that led to HSV-1 reactivation.

This led them to wonder what would happen if they exposed their brain tissue models to a physical disruption similar to a concussion. Will HSV-1 wake up and begin the process of neurodegeneration?

To study, they examined the effects of one or more controlled blows on a 3D human brain tissue model with or without quiescent HSV-1 infection.

After repeated mild, controlled blows, the researchers found that latently infected 3D brain tissue showed HSV-1 reactivation and the production and accumulation of amyloid beta and beta tau, which promote neurodegeneration. discovered. The blow also activated gliosis, which is associated with destructive neuroinflammation.

They noted that these effects are collectively associated with Alzheimer's disease, dementia, and chronic traumatic encephalopathy and increase with further injury, but are absent in tissues not infected with HSV-1.

“These data suggest that HSV-1 in the brain is critical to increased risk of Alzheimer's disease, as other recent studies using brain organoids have suggested.” they wrote.

They found that after brain injury, “the resulting inflammation, whether due to infection or mechanical damage, induces reactivation of HSV-1 in the brain, leading to the development of Alzheimer's disease/dementia.” , HSV-1 in particular is the main cause of the disease. APOE4 carrier. ”

Future research will aim to “reduce or prevent the damage caused by head trauma and thereby, by implementing efforts to prevent reactivation of viruses in the brain, such as post-traumatic anti-inflammatory and/or antiviral treatments. , there is a need to investigate “possible ways to reduce the subsequent development of Alzheimer's disease.” the researchers suggested.

Involvement of external experts

In a statement from the UK non-profit Science Media Center, several external experts provided their views on the research.

Dr Tara Spiers-Jones, president of the British Society for Neuroscience and group leader at the British Dementia Research Institute in London, said the study was interesting but had limitations.

“The increase in Alzheimer's disease-like brain changes in these damaged latent virus-containing cells does not resemble the pathology seen in the brains of Alzheimer's patients,” Spiers-Jones noted.

“These experiments were also performed in cells grown in artificial conditions that do not contain important factors associated with Alzheimer's disease, such as age and vascular changes. Finally, these experiments were performed in small numbers of replicates (each experiment Because these results were repeated three times), a larger study would provide a more relevant biological link to confirm that there is a biological link between the types of latent herpes simplex virus. You need to check it on your own system. 1, brain damage, Alzheimer's disease,'' Spiers-Jones warned.

Robert Howard, MD, MRCPsych, from the Department of Psychiatry at University College London (UCL), London, UK, said the study suggests a possible mechanism for the link between HSV-1, brain damage and Alzheimer's disease. said.

“However, it is very important to keep in mind that, as is often the case in science, association does not imply causation. Much more research will be needed before this happens,” Howard warned.

“We already know that avoiding brain injuries, such as those encountered in some contact sports, is an important way to prevent dementia, but this is more important than mechanical injuries that cause brain cell death. “I'm not convinced that it reflects anything complex,” he added. .

Dr. Jennifer Pocock, from UCL's Queen Square Neurological Institute in London, UK, pointed out that the study did not address the role of microglia, which are activated by mild repetitive traumatic brain injury.

“This paper seems to suggest that astrocytes alone contribute to the neuroinflammation reported in brain tissue. Apoe 3/4 Not clearly defined. Therefore, the findings may represent an overinterpretation of the 'real world', as the inclusion of microglia may negate or accentuate them, depending on the severity of the TBI. “It's very likely that there are,” Pocock said.

This research was funded by the U.S. Army Research Office and the Department of Defense. The authors declare that they have no relevant conflicts of interest. Spiers-Jones and Howard had no relevant disclosures related to this study. Pocock has received research funding from AstraZeneca and Daiichi Sankyo.