GGenetic and lifestyle factors, as well as repeated head trauma, have long been associated with an increased risk of Alzheimer’s disease (AD).1 In contrast, until recently, the hypothesis that viruses such as herpes simplex virus 1 (HSV-1) may contribute to the pathogenesis of AD has received relatively little attention.2
In a new study published in scientific signalResearchers from Tufts University and the University of Oxford used human brain organoids to demonstrate that head injury can reactivate dormant HSV-1 in the brains of carriers of a common genetic variant, triggering the onset of pathological hallmarks of AD.3 These findings support growing evidence that viruses may increase susceptibility to AD or promote AD progression, highlighting their potential role in neurodegenerative processes.
Immunostained image of a brain organoid section containing latent HSV-1 showing neurons (green), nuclei (blue), and abundant beta-amyloid plaques (red) after repeated brain injury.
Dana Cairns
HSV-1 is highly prevalent in the human population, with approximately 80% of people over the age of 60 being infected. . Biophysicist Ruth Itzhaki of the University of Oxford was an early proponent of a link between HSV-1 and AD.4 Yet for decades, her research was met with hostility and largely dismissed.
Dana Cairns, a stem cell biologist in David Kaplan’s laboratory at Tufts University and a co-author of the study, collaborated with Itzhaki to examine the link between HSV-1 and AD from a new perspective. The team speculates that inflammation caused by head injury may trigger the reactivation of latent viruses, leading to the onset of AD. To test their theory, they used brain organoids: three-dimensional cultures that resemble miniature brains.
“They’re really suitable for a lot of different analysis techniques, and because they have a scaffold, they’re very powerful and you can do all kinds of manipulations and different types of damage to them,” Cairns commented.
Keynes and her colleagues created these organoids using induced neural stem cells from humans that carry a copy of the E4 variant of the apolipoprotein E gene.apolipoprotein4), the most common known risk factor for AD.5 After infecting the organoids with HSV-1, they induced latency using antiviral drug treatment to block replication.
After allowing the organoids to mature, they encased them in small prosthetic skulls created with the help of mechanical engineers. “We add fluid to simulate cerebrospinal fluid and then put a cap on it so it actually fits snugly like a skull around the brain,” Cairns said.
Next, the team needed to tap into tiny brains to simulate a real head injury. Cairns and her colleagues used a small piston to deliver precise blows to the skull, causing the brains to push against each other. They then performed immunostaining to look for morphological changes in damaged brains associated with AD and neurodegenerative diseases, including beta-amyloid plaque accumulation.6
The results were more dramatic than Keynes expected. While mock-infected controls did not show significant morphological changes beyond expected injury-related inflammation, organoids with latent HSV-1 exposed to repeated trauma exhibited distinct AD-related phenotypes, such as β-amyloid plaques. piece. Quantitative PCR showed increased HSV-1 transcript levels, confirming reactivation of latent virus.
“When we looked at these brain organoids that were latently infected and then injured, they had these giant plaques, which was really cool,” Keynes said.
The success of the experiment inspired the team, many of whom were novice researchers. “I worked with a group of female undergraduates, and they were very enthusiastic,” Cairns recalled. “Fortunately, these initial pilot experiments worked really well, which makes them very excited to stay in the lab longer!”
“[The authors] Insult the brain and see the effects, and they have all the appropriate controls. “I’m really impressed by the quality of this study,” said Ralph Martins, a biochemist at Macquarie University and an expert on AD who was not involved in the study. “The model’s The results are very convincing.”
Cairns and her team found that HSV-1 reactivation was associated with an increase in the pro-inflammatory cytokine interleukin 1β (IL-1β) in damaged organoids, leading them to wonder whether blocking IL-1β production could prevent AD. Phenotype formation. By scraping the surface of 2D cultures with a needle and treating them with an antibody that blocks IL-1β, they significantly reduced beta-amyloid production.
Cairns said the results could eventually help develop preventive measures for professional athletes who suffered repeated concussions and head trauma at a young age, which they plan to test in future experiments. “[For a concussion] The current standard of care is just rest and maybe occasional painkillers,” she commented. “It seems reasonable to us to consider antiviral treatment as a preventive measure to avoid neurodegenerative diseases in the future.”
However, Martins noted that further research is needed before the results can be translated into AD prevention. “You have to remember this [the model] It’s brains on a plate. It’s not the human brain… but it’s a good step in the direction of seeing if this has an impact,” he commented.
