Summary: Varicella zoster virus (VZV), the virus that causes chickenpox and shingles, can activate the herpes simplex virus and trigger the onset of Alzheimer’s disease, according to a new mouse study.
Source: Tufts University
Alzheimer’s disease can start almost imperceptibly, often masquerading in the first few months or years as a common forgetfulness in older people. What causes the disease remains largely a mystery.
But researchers from Tufts University and the University of Oxford, using a three-dimensional human tissue culture model mimicking the brain, showed that the varicella zoster virus (VZV), which commonly causes chickenpox and shingles , can activate herpes simplex (HSV), another common virus, to trigger the early stages of Alzheimer’s disease.
Normally, HSV-1 – one of the major variants of the virus – lies dormant in brain neurons, but when activated leads to buildup of tau and beta-amyloid proteins and loss of neuronal function – signature features found in patients with Alzheimer’s.
“Our results suggest a pathway to Alzheimer’s disease, caused by a VZV infection that creates inflammatory triggers that arouse HSV in the brain,” said Dana Cairns, GBS12, research associate in the department of biomedical engineering. “Although we demonstrated a link between VZV and HSV-1 activation, it is possible that other inflammatory events in the brain may also trigger HSV-1 and lead to Alzheimer’s disease.”
The study is published in the Alzheimer’s Disease Journal
“We worked through a lot of established evidence that HSV has been linked to an 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 of the first to hypothesize a link between the herpes virus and Alzheimer’s disease is Ruth Itzhaki of the University of Oxford, who collaborated with the Kaplan laboratory on this study.
“We know there is a correlation between HSV-1 and Alzheimer’s disease, and a suggested involvement of VZV, but what we didn’t know was the sequence of events that viruses create to trigger disease,” he said. “We believe we now have evidence of these events.”
According to the World Health Organization, approximately 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, dormant in nerve cells.
When activated, it can cause inflammation of nerves and skin, causing open sores and painful blisters. Most carriers — and that’s one in two Americans according to the CDC — will have between very mild and no symptoms before the virus becomes dormant.
Varicella zoster virus is also extremely common, with around 95% of people becoming infected before the age of 20. Many of these cases manifest as chickenpox. VZV, which is a form of herpes virus, can also remain in the body, finding its way to nerve cells before becoming dormant.
Later in life, VZV can be reactivated to cause shingles, a disease characterized by skin blisters and nodules that form in a band-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 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 can wake up
To better understand the cause-and-effect relationship between viruses and Alzheimer’s disease, Tufts researchers recreated brain-like environments in small, 6-millimeter-wide doughnut-shaped sponges made of silk proteins and of collagen.
They populated the sponges with neural stem cells that grow into functioning neurons capable of transmitting signals to each other in a network, just as they do in the brain. Some of the stem cells also form glial cells, which are usually found in the brain and help keep neurons alive and functioning.
Researchers found that developed neurons in brain tissue can become infected with VZV, but this alone did not lead to the formation of Alzheimer’s tau and beta-amyloid proteins – the components of tangle fibers and plaques that form in Alzheimer’s disease. patients’ brains and that the neurons continued to function normally.
However, if the neurons already harbored quiescent HSV-1, exposure to VZV resulted in HSV reactivation and a dramatic increase in tau and beta-amyloid proteins, and neuronal signals began to slow.
“It’s a double punch of two viruses that are very common and generally harmless, but laboratory studies suggest that if further exposure to VZV awakens dormant HSV-1, they could cause problems,” Cairns said. .
“It is always possible that other infections and other causal pathways could lead to Alzheimer’s disease, and risk factors such as head trauma, obesity or alcohol consumption suggest that ‘they can cross paths during the re-emergence of HSV in the brain,’ she added. added.
The researchers observed that samples infected with VZV began 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 inflammation in the brain, which could eventually lead to activation of dormant HSV and increased inflammation.
Repeated cycles of HSV-1 activation can lead to further inflammation in the brain, plaque production, and accumulation of neuronal and cognitive damage.
A VZV vaccine – to prevent chickenpox and shingles – has also been shown to significantly reduce the risk of dementia. The vaccine may help 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 in the elderly, and that VZV and HSV-1 can be reactivated after COVID infection. Keeping an eye out for possible later cognitive effects and neurodegeneration would be desirable in these cases, they said.
About this Alzheimer’s disease and virology research news
Author: Mike Silver
Source: Tufts University
Contact: Mike Silver – Tufts University
Image: Image is credited to Tufts University
Original research: Access closed.
“Potential involvement of varicella-zoster virus in Alzheimer’s disease via reactivation of quiescent herpes simplex virus type 1” by Dana Cairns et al. Alzheimer’s Disease Journal
Potential involvement of varicella-zoster virus in Alzheimer’s disease via reactivation of quiescent herpes simplex virus type 1
Background: Varicella zoster virus (VZV) has been implicated in Alzheimer’s disease (AD) and vaccination against shingles, caused by VZV, has been shown to decrease the risk of AD/dementia. VZV could reside latently in the brain and, upon reactivation, cause direct damage leading to AD, as proposed for herpes simplex virus type 1 (HSV-1), a virus strongly implicated in the MA. Alternatively, shingles could induce neuroinflammation and therefore the reactivation of HSV-1 in the brain.
Objective: To investigate these possibilities by comparing the effects of VZV and HSV-1 infection on cultured cells, and the action of VZV infection on resting HSV-1 infected cells. Methods: We infected human-induced neural stem cell (hiNSC) cultures with HSV-1 and/or VZV and screened for the presence of Alzheimer’s disease-related phenotypes such as accumulation of amyloid-β (Aβ) and P-tau, gliosis and neuroinflammation.
Results: VZV-infected cells did not show the main hallmarks of AD, the accumulation of Aβ and P-tau, that HSV-1 causes, but did show gliosis and increased levels of pro-cytokines. inflammatory, suggesting that the action of VZV in AD/dementia is indirect. Strikingly, we found that VZV infection of quiescent HSV-1 infected cells causes HSV-1 reactivation and subsequent AD-like changes, including accumulation of Aβ and P -tau.
Conclusion: Our results are consistent with the suggestion that shingles causes HSV1 reactivation in the brain and with the protective effects against AD of various vaccines, as well as with the decrease in cold sores reported after some types of vaccination. They support an indirect role of VZV in AD/dementia via reactivation of HSV-1 in the brain.