Alzheimer’s Disease Triggered by Two Common Herpes Viruses

The symptoms of Alzheimer’s disease, a progressive and debilitating condition that destroys a person’s memories and other mental functions, can at the start be nearly almost imperceptible, often misidentified in the early months or years of the disease as forgetfulness common with older age. The causes of Alzheimer’s have generally remained elusive.

But now, using a three-dimensional human tissue culture model mimicking the brain, researchers at Tufts University and the University of Oxford have shown that varicella zoster virus (VZV), which causes chickenpox and shingles, may activate herpes simplex virus (HSV), which leads to the onset of Alzheimer’s disease. The study is published in the Journal of Alzheimer’s Disease.

Normally, HSV-1 — one of the main variants of the herpes virus — lies dormant within the neurons of one’s brain, but when activated leads to the accumulation of tau and amyloid beta proteins and a loss of neuronal function, primary signs of Alzheimer’s.

“Our results suggest one pathway to Alzheimer’s disease, caused by a VZV infection which creates inflammatory triggers that awaken HSV in the brain,” said Dana Cairns, a research associate in Tufts University’s Biomedical Engineering Department. “While we demonstrated a link between VZV and HSV-1 activation, it’s possible that other inflammatory events in the brain could also awaken HSV-1 and lead to Alzheimer’s disease.”

Researchers “have been working off a lot of established evidence that HSV has been linked to increased risk of Alzheimer’s disease in patients,” said David Kaplan, Stern Family Professor of Engineering and chair of the Department of Biomedical Engineering at Tufts’ School of Engineering.

“We know there is a correlation between HSV-1 and Alzheimer’s disease, and some suggested involvement of VZV, but what we didn’t know is the sequence of events that the viruses create to set the disease in motion,” he said. “We think we now have evidence of those events.”

According statistics from 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, lying dormant within nerve cells.

When the oral herpes virus is activated, it can cause inflammation in nerves and skin, leading to painful open sores and blisters. The Centers for Disease Control estimates 50 percent of all Americans carry the virus, although most of those infected will experience very mild to no symptoms before the virus becomes dormant.

The varicella zoster virus is also extremely common, with about 95 percent of people having been infected before the age of 20. Many of the VZV cases manifest as chicken pox. and again, like the HSV, the VZV can also remain in the body, finding its way to nerve cells before then becoming dormant.

The VZV can be reactivated later in a person’s life to cause shingles, a disease characterized by blisters and nodules in the skin that can be very painful, lasting for weeks and even months. Health experts believe one in three people will develop a case of shingles sometime in their lifetime.

The linkage between HSV-1 and Alzheimer’s only occurs when HSV-1 has been reactivated to cause sores, blisters and other painful inflammatory conditions.

To better understand the cause-and-effect relationship between the viruses and Alzheimer’s, Tufts researchers re-created brain-like environments in small 6 millimeter-wide doughnut-shaped sponges made of silk protein and collagen.

They populated the sponges with neural stem cells that are able to grow into functional neurons capable of passing signals to each other in a network, just as they do in the brain.

The researchers found that neurons grown in the brain tissue can be infected with VZV, but that alone did not lead to the formation of the signature tau and beta-amyloid Alzheimer’s proteins  and that the neurons continued to function normally.

However, if the neurons already harbored HSV-1, the exposure to VZV led to a reactivation of HSV, and a dramatic increase in tau and beta-amyloid proteins, followed by neuronal signals beginning to slow down.

“It’s a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble,” said Cairns.

“It’s still possible that other infections and other pathways of cause and effect could lead to Alzheimer’s disease, and risk factors such as head trauma, obesity, or alcohol consumption suggest they may intersect at the re-emergence of HSV in the brain,” she added.
The researchers observed that the VZV infected samples started to produce a higher level of cytokines, proteins often involved in triggering an inflammatory response. Kaplan noted that VZV is known in many clinical cases to cause brain inflammation, which could lead to activation of dormant HSV and increased inflammation.

Repeat cycles of HSV-1 activation can lead to more inflammation in the brain, production of plaques, and accumulation of neuronal and cognitive damage.

A vaccine for VZV — to prevent chickenpox and shingles — has also been shown to considerably reduce the risk of dementia. The vaccine, researchers suggested, is helping to stop the cycle of viral reactivation, inflammation, and neuronal damage.

The study team also noted the long-term neurological effects some COVID patients have experienced from the SARS-CoV-2 virus, particularly among the elderly. Both the VZV and HSV-1 can be reactivated after a COVID infection.