Today more than 55 million people around the world have Alzheimer’s disease and other dementias, which ravage the minds of those who suffer from them and have devastating impacts on their family members. In spite of decades of research, the precise origins of these diseases continue to elude scientists, though numerous factors have been found to be associated with higher risk, including genetics and various lifestyle and environmental factors.
The quest has recently taken a turn to a newer model for studying the brain: brain organoids. These three-dimensional clumps of neuronal tissue derived from human stem cells can mature into differentiated cells and have been used to study everything from epilepsy to the origins of consciousness. And now, researchers in Massachusetts are slamming them with miniature metal pistons to test out whether they can lend credence to a novel hypothesis: that concussions might reactivate a common virus in the brain, increasing dementia risk.
A decade of research suggests traumatic brain injury, whether from accidents or high-contact sports, is a standout risk factor for Alzheimer’s and other forms of neurodegenerative decline. Some estimates suggest that up to 10 percent of cases could be attributed to at least one prior head injury, but why is not fully understood. Separately, a growing body of research proposes that viral infection, including a common virus known as herpes simplex one, can also increase susceptibility to these diseases. But all three things—head trauma, viral infection, and dementia—have not been directly connected in experimental research, until now.
One of the challenges in getting to the roots of dementia is that humans lead complex, messy lives. In the soup of risk factors—from high blood pressure to loneliness to genetic inheritance—it can be hard to filter out the most impactful forces that have contributed to the onset of any one dementia case. There are no ethical ways to test these questions on humans, of course, while using lab animals presents its own ethical and cost challenges. Animals are never a perfect match for humans anyway, and dementia-related findings in animals have so far not translated well to human patients.
Enter the organoids.
In lab-grown brain organoids, scientists have been able to model some of the same hallmarks of neurodegenerative disease found in the autopsied brains of humans who suffered these diseases while they were alive. These include accumulations of beta amyloid protein, a metabolic waste product, into structures known as plaques, which disrupt signaling between nerve cells.
The more blows these tiny organoids took, the more abnormal structures the scientists found.
For the new lab study, a team of researchers grew a series of brain organoids. Some of the organoids had a dormant form of herpes simplex virus—which exists in 80 percent of people by age 60—while others were virus-free. Then they jolted all of the brain organoids with two different kinds of tiny metal pistons, a model that has been used by other scientists to mimic head trauma in brain organoids.
“We think what we found in the 3-D model applies in the living brain,” says Ruth Itzhaki, a visiting professorial fellow at the University of Oxford and co-author on the new study, which was published this month in the journal Science Signaling. “You get a reactivation of the virus after each blow, and each time damage is done. It all accumulates until, eventually, you get Alzheimer’s.”
In the model organoids that were infected with the virus, after repeated blows to the brain tissue, the dormant viruses woke up and started replicating again. Later, some of the signatures of Alzheimer’s and other dementias began to appear: in particular proliferation of beta-amyloid protein and neuroinflammation. The more blows these tiny organoids took, the more inflammation and beta amyloid the scientists found.
The organoids without any dormant virus only showed a few minor changes after they were hit with the piston, such as an increase over 10 days in the number of glial cells, which act like scar tissue in the brain after an injury. The researchers concluded that repeated blows to the head may contribute to dementia by reactivating latent herpes simplex virus.
Itzhaki started investigating the role of herpes simplex virus in Alzheimer’s disease more than 30 years ago. She was part of a team who first discovered herpes simplex virus in the autopsied brain tissue of elderly people, both with and without Alzheimer’s disease. At the time, brain tissue was considered sterile, or microbe-free.
Her team went on to discover that in cell culture, the virus could lead to key Alzheimer’s features—amyloid plaques and protein tangles inside nerve cells, which also disrupt signaling—particularly in people who carried the heritable APOE4 gene. The researchers also found that these same features could be reduced with antivirals. They later found that the varicella zoster virus, responsible for chicken pox and shingles, can also reactivate latent herpes simplex virus in a three-dimensional brain model.
Itzhaki says that despite decades of hostility against the idea that Alzheimer’s could be caused by a virus, support for the link has grown in recent years. Viruses cause not only direct damage, but also inflammation—which switches on other latent viruses. “It becomes a vicious cycle with inflammation,” she says.
David Corry, a professor of pathology and immunology and medicine at Baylor College in Houston, Texas, says the findings are the first to show that repetitive head injury is a convincing trigger for reactivating latent herpes simplex virus and promoting brain changes associated with dementias. Based on the data presented, he agrees with the conclusions Itzhaki and her team made.
“This study suggests that a unifying feature of these [neurodegenerative] disorders might be the reactivation of herpes simplex virus one, but possibly also other brain infections that are only now coming to light,” says Corry. Of course, a brain organoid is not a brain, says Corry, so it does not have an immune system or other reparative processes available to it that might help to mitigate damage done by head trauma or virus re-activation.
And there are likely many paths to the development of these complex diseases of the brain. When doctors autopsy the brains of people who were diagnosed, they often see many different types of pathologies in various regions of their brains, which may indicate different potential causes, such as genetics, lifestyle factors, and age-related brain changes, says Brian Balin, a neuroscientist at the Philadelphia College of Osteopathic Medicine. But collecting a complete history of patients’ injuries and infections could help doctors diagnose dementia or Alzheimer’s disease and lead to earlier interventions, he says.
Itzhaki says in the future she wants to look into how to interrupt the damaging processes that unfold following traumatic brain injuries, such as those suffered in soccer, boxing, and football. She is aiming to test antivirals and other medications to reduce the inflammation caused by viruses that could be reactivated after a brain injury.
Though they are far from a perfect proxy, brain organoids will help her and others to continue this work.
Lead image: Alphavector / Shutterstock
Get the Nautilus newsletter
Cutting-edge science, unraveled by the very brightest living thinkers.
