A new study shows that the brains of Alzheimer’s disease patients have a greater viral load, while another study in mice shows infection leads to amyloid-β build up
Even a century after is discovery, Alzheimer’s disease (AD) remains one of the most confounding illnesses known to humanity. The brains of AD patients have an abnormal buildup of amyloid-β proteins and tau tangles, which, according to many researchers, drives the ultimately fatal cognitive disease. No effective treatment or prevention exists that could perturb the progressive deterioration of brain tissue, memory and identity. With an increase in life expectancy, it is the need of the hour is to find an explanation for the risk factors and disease mechanisms.
One of the fringe theories of Alzheimer’s disease pathogenesis has challenged the existing notion. It states that latent viral infections trigger its emergence and has perhaps gotten its most significant bits of support recently with two published studies. Scientists have provided evidence that certain species of human herpesvirus contribute to AD development. High levels of human herpesvirus 6A and 7 were found in brain samples showing signs of Alzheimer’s neuropathology. In addition, they may also play a direct role in the acceleration of this fatal neurodegeneration.
In the first study published in Neuron on June 21, researchers under the supervision of Joel Dudley at Icahn School of Medicine at Mount Sinai, New York analyzed the post-mortem brain samples from patients with Alzheimer’s disease and found that two strains of human herpesvirus are significantly more abundant than in their brains as compared to non-diseased people of the same age. Gene networks in the brains of Alzheimer’s patients with these strains are also rewired such that disease-related genes are differentially expressed compared to controls.
“We actually had no intentions of looking at this theory. We were actually looking for new drug targets,” Dudley remarked. “But by taking this data-driven approach on an exciting new data set, we were led down this path of looking at viruses.”
Dudley’s team sequenced more than 1,400 post-mortem brain samples, finding the first evidence that human herpesviruses 6A (HHV-6A) and 7 (HHV-7) are in greater abundance in regions of the brain including the superior temporal gyrus, anterior prefrontal cortex, and dorsolateral prefrontal cortex. Using computational models, the team also generated regulatory network models that implicated the presence these viruses in altering the activity of genes linked to Alzheimer’s risk. HHV-6A seemed to be suppressing microRNA-155 as well. Knocking out the gene for miR-155 lead to mice brains’ with larger amyloid plaques and higher levels of amyloid-b compared to the control.
“The conclusion you can draw is that the antiherpes medication reduced the risk of Alzheimer’s by keeping the herpes infection in check,” says Moir.
In the other study conducted by the groups of Rudolph Tanzi and Robert Moir, both researchers at Harvard Medical School and Massachusetts General Hospital, tested how amyloid-b in the brain reacts to herpes simplex virus 1 (HSV1), HHV6A, and HHV6B. They found that in a culture of human neuronal cells, amyloid-β could prevent HSV1 infection and can bind and aggregate the HSV1 and HHV6 viruses. Mice infected with HSV1—which can cause encephalitis—that also had genetically elevated amyloid-β expression were protected against encephalitis, but also had increased amyloid deposits. Their results are available as a pre-print on the Cell website.
These herpes viruses are extremely common, and can cause a skin rash called roseola in young children. But the viruses also can get into the brain, where they may remain inactive for decades.
“These two papers add to a weight of evidence that viruses—and pathogens in general—must now be seriously considered as causal agents in Alzheimer’s disease,” Chris Carter, who studies the genetics and epidemiology of Alzheimer’s and other neurological disorders at Polygenic Pathways in the U.K., tells The Scientist. He also cautions that the new reports should not be interpreted to mean that there is likely a single, unique Alzheimer’s pathogen, if there is one at all.
A recent epidemiology study adds real-world credence to the microbial link to Alzheimer’s. A population study in Taiwan examined more than 33,000 individuals and found that those with a herpes simplex virus infection had a 2.5-fold greater risk of developing Alzheimer’s disease. The study authors found that in those people treated with antiherpes medications, the 2.5-fold risk dropped back down to baseline.
The conclusions have also been met with skepticism. According to Dr. Richard Hordes, director of the National Institute on Aging, “The data are very provocative, but fall short of showing a direct causal role,” he says. “And if viral infections are playing a part, they are not the sole actor.”
“It’s analogous to what happens with the gut microbiome in individuals with irritable bowel syndrome,” says Moir. “Our model right now is that it’s not just a single microbe, but a disturbance in the brain microbiome that can lead to Alzheimer’s disease.”
Tanzi’s and Moir’s labs are focusing on the role of the brain microbiome in Alzheimer’s disease. Comparing the brains of older and younger individuals, including those with Alzheimer’s, their preliminary evidence shows that the brain microbiome—which contains hundreds of bacterial and fungal species—is shifted and linked to pro-inflammatory activity.
Most previous efforts to prevent or treat Alzheimer’s have involved trying to reduce the plaques and tangles associated with the disease. Those efforts have failed to improve brain function. The more we learn about the disease process, the more targets we can address and the greater the probability we are going to slow or prevent the progression of Alzheimer’s disease.