Common viruses may be the cause of the emergence of

Image: Varicella-zoster virus (VZV), which usually causes chickenpox and shingles, activates herpes simplex virus (HSV) from dormancy in lab-grown nerve tissue, which then leads to increased plaque deposits and a decrease in nerve signals – hallmarks of Alzheimer’s disease illness.
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Credit: Tufts University

Alzheimer’s disease can begin almost imperceptibly, often disguised in the early months or years as forgetfulness common in the elderly. The cause of the disease remains largely a mystery.

But researchers at Tufts University and Oxford University, using a 3-D model of human tissue culture simulating the brain, have shown that varicella-zoster virus (VZV), which commonly causes chickenpox and shingles, may activate herpes simplex (HSV), another virus. A common virus, to trigger the early stages of Alzheimer’s disease.

HSV-1 – one of the main variants of the virus – is usually latent within brain neurons, but when activated it leads to a buildup of tau and amyloid-beta proteins and a loss of neuron function – hallmarks found in patients with Alzheimer’s disease.

“Our results indicate a single pathway in Alzheimer’s disease, caused by VZV infection that creates inflammatory triggers that awaken HSV in the brain,” said Dana Kearns, GBS12, a research assistant in the Department of Biomedical Engineering. “While we have demonstrated a link between VZV and HSV-1 activation, it is possible that other inflammatory events in the brain can also awaken HSV-1 and lead to Alzheimer’s disease.”

The study was published in Alzheimer’s Disease Journal

Viruses are waiting

“We’ve worked on a lot of solid evidence that HSV is associated with an increased risk of Alzheimer’s disease in patients,” said David Kaplan, Stern family professor of engineering and chair of the biomedical engineering department at Tufts School of Engineering. One of the first to hypothesize a link between the herpes virus and Alzheimer’s disease was Ruth Itzaki of the University of Oxford, who collaborated with Kaplan’s lab on this study.

“We know there is an association between HSV-1 and Alzheimer’s disease, and some have suggested VZV is involved, but what we didn’t know was the sequence of events that viruses create to trigger the disease,” he said. “We believe we now have evidence of those events.”

According to the World Health Organization, an estimated 3.7 billion people under the age of 50 have been infected with HSV-1 – the virus that causes oral herpes. In most cases, it is asymptomatic, and is latent within the neurons.

When activated, it can cause inflammation in the nerves and skin, causing painful open sores and blisters. Most carriers of the virus — that’s one in two Americans according to the CDC — will have very mild to no symptoms before the virus becomes latent.

Varicella-zoster virus is very common, with about 95 percent of people infected before the age of 20. VZV, a form of the herpes virus, can also remain in the body, finding its way into nerve cells before it goes dormant.

Later in life, VZV can reactivate to cause herpes zoster, a disease characterized by blisters and nodules in the skin that form in a gang-like pattern and can be very painful and last for weeks or even months. One in three people will eventually develop a case of shingles in their lifetime.

The association between HSV-1 and Alzheimer’s disease occurs only when HSV-1 is reactivated to cause sores, blisters, and other painful inflammatory conditions.

How do dormant viruses wake up

To better understand the cause-and-effect relationship between viruses and Alzheimer’s disease, Tufts University researchers have recreated brain-like environments in a small, 6-millimeter-wide doughnut-shaped sponge made of silk protein and collagen.

They filled the sponge with neural stem cells that grow into functional neurons capable of passing signals to each other in a network, just as they do in the brain. Some stem cells also form glial cells, which are normally found in the brain and help keep neurons alive and working.

The researchers found that neurons growing in brain tissue could be infected with VZV, but that alone did not lead to the formation of the Alzheimer’s signature proteins tau and beta-amyloid – components of the messy tangled fibers and plaques that form in Alzheimer’s disease. patients’ brains — and that neurons continued to function normally.

However, if neurons already contained quiescent HSV-1, exposure to VZV resulted in HSV reactivation, a significant increase in tau and beta-amyloid proteins, and neuronal signaling begins to slow.

“It’s one or two hits from two very common and usually harmless viruses, but lab studies suggest that if new exposure to VZV wakes up dormant HSV-1, it can cause problems,” Kearns said.

“It is still possible for other infections and other pathways of cause and effect to lead to Alzheimer’s disease, and risk factors such as head trauma, obesity or alcohol consumption suggest that they may intersect when HSV re-emerges in the brain,” he added.

The researchers observed that samples infected with VZV began to produce a higher level of cytokines – proteins often involved in triggering the inflammatory response. In many clinical cases, Kaplan noted, the herpes simplex virus is known to cause inflammation in the brain, which may lead to reactivation of the dormant herpes simplex virus and increased inflammation.

Repeated cycles of HSV-1 activation can lead to more inflammation in the brain, the production of plaques, and a buildup of neurological and cognitive damage.

The VZV vaccine – to prevent chickenpox and shingles – has been shown to significantly reduce the risk of developing dementia. The vaccine likely helps stop the virus’ reactivation cycle, inflammation and nerve cell damage.

The researchers also noted the long-term neurological effects that some COVID patients experienced from SARS-CoV-2, especially among the elderly, and that both VZV and HSV-1 can be reactivated after COVID infection. Monitoring for follow-up cognitive effects and neurodegeneration is advisable in these cases, they said.

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