Alzheimer’s disease can begin almost imperceptibly, often masquerading within the early months or years as forgetfulness that’s common in older age. What causes the disease stays largely a mystery.

But researchers at Tufts University and the University of Oxford, using a three-dimensional human tissue culture model mimicking the brain, have shown that varicella zoster virus (VZV), which commonly causes chickenpox and shingles, may activate herpes simplex (HSV), one other common virus, to set in motion the early stages of Alzheimer’s disease.

Normally HSV-1 – one in every of the principal variants of the virus – lies dormant inside the neurons of the brain, but when it’s activated it results in accumulation of tau and amyloid beta proteins, and lack of neuronal function-;signature features present in patients with Alzheimer’s.

Our results suggest one pathway to Alzheimer’s disease, brought on by a VZV infection which creates inflammatory triggers that awaken HSV within the brain. While we demonstrated a link between VZV and HSV-1 activation, it’s possible that other inflammatory events within the brain could also awaken HSV-1 and result in Alzheimer’s disease.”

Dana Cairns, GBS12, research associate, Biomedical Engineering Department

The study is published within the Journal of Alzheimer’s Disease

Viruses lying in wait

“We’ve got been working off lots 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. One in all the primary to hypothesize a connection between herpes virus and Alzheimer’s disease is Ruth Itzhaki of the University of Oxford, who collaborated with the Kaplan lab on this study.

“We all know there may be a correlation between HSV-1 and Alzheimer’s disease, and a few 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 predict we now have evidence of those events.”

In accordance with the World Health Organization, an estimated 3.7 billion people under the age of fifty have been infected with HSV-1-;the virus that causes oral herpes. Most often it’s asymptomatic, lying dormant inside nerve cells.

When activated, it may possibly cause inflammation in nerves and skin, causing painful open sores and blisters. Most carriers-;and that is one in two Americans based on the CDC-;may have between very mild to no symptoms before the virus becomes dormant.

Varicella zoster virus can also be extremely common, with about 95 percent of individuals having been infected before the age of 20. Lots of those cases are expressed as chicken pox. VZV, which is a type of herpes virus, can even remain within the body, finding its strategy to nerve cells before then becoming dormant.

Later in life, VZV will be reactivated to cause shingles, a disease characterised by blisters and nodules within the skin that form in a band-like pattern and will be very painful, lasting for weeks and even months. One in three people will eventually develop a case of shingles of their lifetime.

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

How sleeping viruses may wake

To raised understand the cause-and-effect relationship between the viruses and Alzheimer’s disease, the Tufts researchers re-created brain-like environments in small 6 millimeter-wide donut-shaped sponges manufactured from silk protein and collagen.

They populated the sponges with neural stem cells that grow and change into functional neurons able to passing signals to one another in a network, just as they do within the brain. A number of the stem cells also form glial cells, that are typically present in the brain and help keep the neurons alive and functioning.

The researchers found that neurons grown within the brain tissue will be infected with VZV, but that alone didn’t result in the formation of the signature Alzheimer’s proteins tau and beta-amyloid-;the components of the tangled mess of fibers and plaques that form in Alzheimer’s patients’ brains-;and that the neurons continued to operate normally.

Nevertheless, if the neurons already harbored quiescent HSV-1, the exposure to VZV led to a reactivation of HSV, and a dramatic increase in tau and beta-amyloid proteins, and the neuronal signals begin to decelerate.

“It is a one-two punch of two viruses which might be quite common and frequently harmless, however the lab studies suggest that if a recent exposure to VZV wakes up dormant HSV-1, they may cause trouble,” said Cairns.

“It’s still possible that other infections and other pathways of cause and effect could lead on to Alzheimer’s disease, and risk aspects similar to head trauma, obesity, or alcohol consumption suggest they might intersect on the re-emergence of HSV within the brain,” she added.

The researchers observed that the VZV infected samples began to supply the next level of cytokines-;proteins which are sometimes involved in triggering an inflammatory response. Kaplan noted that VZV is understood in lots of clinical cases to cause inflammation within the brain, which could possibly result in activation of dormant HSV and increased inflammation.

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

A vaccine for VZV-;to forestall chickenpox and shingles-;has also been shown to considerably reduce the chance of dementia. It’s possible that the vaccine helps to stop the cycle of viral reactivation, inflammation, and neuronal damage.

The researchers also noted the long-term neurological effects that some COVID patients have experienced from the SARS-CoV-2 virus, particularly among the many elderly, and that each VZV and HSV-1 will be reactivated after a COVID infection. Keeping track of possible follow-on cognitive effects and neurodegeneration could be advisable in these cases, they said.

Source:

Journal reference:

Cairns, D.M., et al. (2022) Potential involvement of Varicella Zoster Virus in Alzheimer’s Disease via reactivation of quiescent Herpes Simplex Virus Type 1. Journal of Alzheimer s Disease. doi.org/10.3233/JAD-220287.