The researchers studied how neurons in mice responded to the presence of herpes simplex 1 (HSV-1), the virus that causes cold sores. In a separate experiment involving a 3D model of the human brain grown in a dish, they also studied human herpesvirus 6 (HHV-6), the germ responsible for causing the childhood skin disease roseola. These viruses are usually caught early on in life and stay dormant somewhere in the body, but as we age, they almost always migrate up to the brain.
Some of the mice used in the experiment were genetically bred to have neurons that could create the human version of amyloid beta (or amyloid-β). Amyloid-β is a protein normally produced in the brain. But in Alzheimer’s patients, it clumps together to form the plaques that are thought by many experts to slowly destroy the brain. Many scientists had long assumed that amyloid-β was essentially a waste product, with no meaningful purpose. But the researchers had earlier shown that amyloid-β might actually serve as a first line of defense against fungal and bacterial infection.
In the current study, both viruses seemed to provoke an identical reaction. The mice’s brains grew new deposits of amyloid-β plaques practically “overnight,” according to senior author Rudy Tanzi, a geneticist specializing in the brain at Massachusetts General Hospital as well as Harvard Medical School. And the mice bred with these human-like neurons were able to better fend off brain infection than mice without them. The same effects were also seen in the petri dish.
“The seeding of amyloid is what causes the deposition of plaque,” Tanzi told Gizmodo, “and herpesviruses and other microbes can rapidly seed amyloid-β.”
The study is the second in recent weeks to support the role of viruses in Alzheimer’s disease. That first study, also published in Neuron and led by researchers from the Icahn School of Medicine at Mount Sinai, found evidence that certain herpesviruses are more abundantly present in the brains of people who died with Alzheimer’s; it also suggested that genes belonging to these viruses directly interact with human genes that raise the risk of the disease.
The timing is no accident, Tanzi said. His team has corresponded with the Mount Sinai team for years, and they had originally planned to release their results at the same time (both will be published in the same print July edition of the journal). It was the Mount Sinai team, Tanzi notes, that suggested the Harvard team look at HHV-6 as well as HSV-1 in their experiments, since that was the virus they had started to zero in on in their work.
While Tanzi and his team acknowledge the long-ignored work by other researchers supporting the viral hypothesis of Alzheimer’s, as it’s known, he said their research takes things in a slightly different direction. It’s an attempt to reconcile various theories about what causes Alzheimer’s.
Supporters of the viral theory have often speculated that germs such as HSV-1 - the most commonly blamed culprit - directly goad the brain into spiraling out of control through inflammation, with amyloid-β only being a bystander. But in Tanzi’s version, amyloid-β still is the key cog behind the disease. Neurons use the protein to either kill or safely trap viral or bacterial particles in a “nano-net,” as Tanzi put it. In Alzheimer’s disease, this process goes off the rails, leading to the uncontrolled buildup of plaques. From there, Tanzi’s work has shown, the plaques trigger the production of tangles - clumps of another brain protein called tau seen in the later stages of Alzheimer’s - which together then trigger chronic inflammation. All of these moving parts align to wither the brain, eventually causing death.
In this scenario, it’s not so much the germ, but the immune system that’s at fault. “The microbes are the prequel to the amyloid hypothesis,” Tanzi said.
Viruses are only one of the things that could set off Alzheimer’s, he pointed out. The same sort of seeding might happen in people whose genes cause them to make too much amyloid-β, in the absence of infection. And genetics might help explain why only some people’s infections cause the brain to start producing amyloid-β en masse. “Just having the virus isn’t enough,” Tanzi said.
But given the widespread failure of Alzheimer’s treatments that have focused on stopping amyloid-β production, the viral link provides a new, clear direction for future clinical trials: Preventative antimicrobial drugs or vaccines that can stop these germs from ever reaching the brain in the first place. Some recent, if observational research (meaning, not controlled trials) has already suggested that these drugs can lower the risk of dementia.
These sorts of definitive studies are likely still a while away, but there’s certainly a change in the headwinds.
“I think we’ve gotten past the point where this idea is ridiculed, but some might be still violently opposing it,” Tanzi said, referring to the 19th century German philosopher Arthur Schopenhauer’s maxim about the three stages of truth (first ridicule, then violent opposition, and finally acceptance as self-evident).
The buck probably won’t stop with herpes either. Tanzi and his team are already at work conducting research on how the bacteria living in the brain could contribute to Alzheimer’s. Tanzi is also part of a research project that is attempting to map out the living microbial universe, or microbiome, of the brain, and how it might influence our mental and physical health.
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