A small 3D version of the human brain develops key features of Alzheimer’s disease when it is infected with a virus that causes cold sores, scientists reported on Wednesday, adding to the evidence that this most common form of dementia can be caused by a common microbe.

The new research, published in Science Advances, is the first to directly show in a lab model (rather than through circumstantial evidence from human studies) that the herpes simplex virus HSV-1 might cause Alzheimer’s: Human brain-like tissue infected with the virus became riddled with amyloid plaque-like formations — the hallmark of Alzheimer’s. It also developed neuroinflammation and became less effective at conducting electrical signals, all of which happen in Alzheimer’s disease.

“This is a very important paper,” said Dev Devanand, chief of geriatric psychiatry at Columbia University College of Physicians and Surgeons, who was not involved in the study and is leading a clinical trial to see whether antiviral drugs can treat mild Alzheimer’s. The HSV-1 findings “support the role of viruses in Alzheimer’s disease.”

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Although a few researchers have long pursued a “microbial theory” of Alzheimer’s, their work has been a backwater, with the scientists struggling to get grants and published. Instead, most scientists focused on the amyloid plaques, which accumulate between brain neurons, as the likely cause, along with tau tangles that spread inside the neurons. That has started to change, with the National Institutes of Health last year inviting scientists to apply for funding to study the role of pathogens in Alzheimer’s.

An estimated 5.8 million people in the U.S., and 50 million worldwide, have the disease. No Alzheimer’s drug has been approved since 2003, and the five on the market don’t even affect the underlying disease.

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The new study used a three-dimensional, engineered human quasi-brain developed by postdoctoral fellow Dana Cairns of Tufts University. She starts with skin cells from human foreskin, then uses genetic techniques to turn them into neural stem cells, which within four days become neurons, glia, and the rest of the neural menagerie in the brain. The key step: putting the cells — 1 million of them — into tiny, donut-shaped sponges made out of silk proteins, a material that neural stem cells apparently take to like algae to a sunny pond.

The result is not a brain “organoid” per se; it does not replicate that organ’s structures. “We call it a tissue-engineered system,” said senior author David Kaplan of Tufts. Measuring 0.2 to 0.4 of an inch across and just under 0.1 of an inch high, it has neurons with axons and dendrites that transmit and receive electrical signals; synapses, where neurons connect; and “amazing networks,” Kaplan said — “the whole deal.”

After normal human brain tissue growing in a lab dish (left) is infected with a virus, it develops abnormalities like those in Alzheimer’s, including amyloid-plaque-like filaments (right). Courtesy Science Advances

Once the lilliputian quasi-brains were up and running, the scientists infected them with HSV-1. Within days, the neural cells developed dense, plaque-like globs similar to the amyloid plaques in Alzheimer’s patients. Inflammation levels soared, and cells fused into abnormal clumps, also as happens in Alzheimer’s. The brain cells began producing higher quantities of the proteins PSEN1 and PSEN2, which raise the risk of Alzheimer’s. And the neurons’ ability to send and receive electrical signals, which underlie all mental processes, crashed.

“These were profound changes, and all these responses — the physiological changes and the functional degradation — are important for the disease,” Kaplan said. “And these were just normal cells”: The scientists didn’t stack the deck by using cells containing genetic variants that raise the risk of Alzheimer’s. “I don’t think anyone has shown these kind of responses to HSV-1, not in a way that shows direct causality,” he said.

Neuropathologist Ruth Itzhaki of the University of Manchester in England, who has studied the role of microbes in causing Alzheimer’s, agreed, calling the research “a really important development.” She said the Tufts team, by showing that HSV-1 causes the “formation of structures closely resembling the characteristic AD plaques and tangles,” demonstrated directly what before now had been only inferred: that the human brain’s response to HSV-1 and other viruses might be what gets Alzheimer’s disease going years before symptoms, and that the plaques and other pathology that most people thought caused the disease are instead a defensive response to the true cause.

That might seem to suggest that antivirals will never be effective against Alzheimer’s: The damage is long since done. That’s what Devanand’s clinical trial is designed to find out. But the 3D quasi-brains offer reason for optimism. When the scientists added the herpes drug valacyclovir, which GlaxoSmithKline sells as Valtrex, the brain tissue became less inflamed, eliminated many of the plaque-like deposits, and functioned better.

Several studies have linked HSV-1 (which lives quietly and, usually, innocuously, in the nervous system) and other herpesviruses to Alzheimer’s, finding, for example, high levels of viral genomes in areas of the brain ravaged by Alzheimer’s and donated to science. That supported the idea that the brain responds to a viral invasion by producing amyloid, which seems to be antimicrobial but may also destroy synapses.

“Active [herpes] infection may not be a requirement for Alzheimer’s disease,” Kaplan and his colleagues wrote. A history of herpes infection might be “sufficient to initiate Alzheimer’s.”

But not in everyone. An estimated two-thirds of people 50 and younger are infected with HSV-1. Although nothing close to that number will develop Alzheimer’s from a virus or anything else, scientists aren’t sure what combination of genetics, lifestyle, and other factors determines who will.

  • This is fascinating information. Two questions.
    1. Have the authors looked into Herpes II.
    2. Do the authors think there is a place for prophylactic treatment with
    Acyclovir or other anti viral drugs

    I would be very interested to see a study that showed the benefit or lack of benefit in people with know herpes infection treated indefinitely with the antiviral.

  • Interesting article. My husband has AD that runs in his family. He also picked up herpes while in the Navy in the late 60 which was treated with antibiotics but did no good. Herpes was basically a new STD then. He was diagnosed in 2008 with AD at age 60. Now I wonder if there is a connection between the herpes and his AD besides family history.

    • Yeah, antibiotics would do no good. They are for bacterial infections. Herpes is a virus.

  • Welp, I guess that means anyone who has had Chicken Pox is doomed. As we all know CP is herpes.

    My humble take, no one has a clue and as long as we continue down the current path in research, no one will ever have a clue.

    • There are many conditions under the ‘herpes’ name. Cold sores are one.

      I honestly believe there are more than one cause of Alzheimer’s, so who knows if they will ever be able to find the one cure. But hopefully some day they can come up with successful treatments.

    • Thank goodness Nobel prizes require far deeper research, indisputable proof, and a solution. The above research is just a good start of something that seems worth pursuing.

  • Dear Ms Begley – I’ve been a big fan of your work for some time now. I’ve given numerous copies of your book on mind training to people suffering from depression and it was universally well received. By chance I stumbled on the stat news site and it’s wonderful to be able to access your excellent work on a daily basis. Keep up the great work! Hope you publish a new book soon.

    Most sincerely,

    Mike Burch

    • Does that extend to those of us who had chicken pox as it seems to be strongly related?

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