Herpes and Alzheimer's: the link is proven
Herpes virus caused symptoms of Alzheimer's disease in a three-dimensional model of the brain
Polina Loseva, N+1
American biologists have deepened our understanding of how herpes and Alzheimer's disease are related: this time they infected a three-dimensional model of brain tissue with the herpes virus. It turned out that the model behaves in the same way as the tissue from the brain of patients with Alzheimer's disease: neurons degenerate, lose electrical activity and become overgrown with auxiliary cells. And although it is too early to say that the virus causes the disease directly, it is already clear that they are firmly linked. The work was published in the journal Science Advances (Cairns et al., A 3D human brain–like tissue model of herpes-induced Alzheimer's disease).
There are many factors that increase the risk of developing Alzheimer's disease – among them not only old age and female sex, but also Down syndrome, obesity, social passivity and many others. But the immediate cause, which is responsible for the appearance of amyloid plaques in the brain, has not yet been identified. Pathogens are often suggested for the role of the culprit – for example, intestinal microbes or bacteria from the oral cavity. In addition to them, the culprit is sometimes called the herpes virus. If these suspicions are confirmed, it will turn out that almost all people on Earth are at risk – since from 70 to 90 percent of the population, according to various estimates, carry it asymptomatically in the nervous tissue.
Until now, it was believed that the role of herpes in the development of Alzheimer's disease is purely mechanical – the viral particle serves as a crystallization center around which deformed amyloid peptides aggregate. However, this is not enough to consider the virus the cause of the disease, at best – a mechanical catalyst. Therefore, a group of researchers from Tufts University, led by David Kaplan, undertook to find out how a herpes infection affects neurons and their microenvironment.
The scientists worked with a three-dimensional model of nervous tissue, which they constructed according to their own design. It was based on a framework of silk protein, filled with collagen gel. The researchers populated this framework with induced neural stem cells – these are fibroblasts that are directly reprogrammed into the precursors of nervous tissue. In culture, they spontaneously differentiated into both neurons and auxiliary cells – neuroglia.
To begin with, the authors of the work checked how an ordinary, non-three-dimensional culture of induced cells reacts to infection. They infected cells with the herpes virus in different concentrations: the ratio of the number of viral particles to the number of cells was 0.01, 0.1 or 1. It turned out that in the maximum concentration per day, the virus infects all cells in the culture, but even in the minimum it penetrates into about every fifth cell. However, the consequences of such infection turned out to be different: the maximum concentration of the virus caused the death of almost a quarter of the cells in the culture, but if you use an even lower concentration – 0.0001 viral particles per cell – then the neurons do not die, but merge with each other, forming complex multicore structures with processes.
Infected culture cells. Red staining – herpes, blue – cell nuclei, green – tubulin, a marker of neurons. On the left is the control culture, then from left to right the dose of the virus increases. Drawings from an article in Science Advances.
By staining these structures with antibodies to beta-amyloid, the researchers found that infected cells produce amyloid fibrils – filaments, from which amyloid plaques are then formed. In addition, infected neurons also expressed proteins for the production of beta-amyloid – the enzymes BACE and PSEN, as well as the protein tau, which is also involved in the pathogenesis of Alzheimer's disease. In addition, after a few days of cultivation, other signs of the disease appeared in the tissue: for example, neuroinflammation (increased levels of pro-inflammatory proteins) and reactive gliosis. At the same time, the supporting glial cells begin to multiply actively and their number, judging by the markers, increased from 9 to 71 percent after infection.
Control culture (left) and infected with herpes (right). Green staining – herpes virus, blue – cell nuclei, red – beta-amyloid. A large "cell" with appendages in an infected culture is the result of the fusion of several neurons.
But if the herpes virus really provokes the symptoms of Alzheimer's disease, then an antiviral drug should prevent them. Indeed, when valacyclovir was added to the culture along with a dose of the virus, the amount of beta-amyloid and its producing enzymes in the cells did not differ from the control. If valacyclovir was added every other day, the improvement was also noticeable, but it was not possible to restore the phenotype of the cells completely. However, this effect of the drug disappeared when the cells were affected not by the virus itself, but by the culture medium of infected cells: in this case, gliosis could not be prevented. This means that not only the virus itself, but also the reaction of cells to its presence triggers a cascade of processes in the tissue that is not so easy to stop.
Finally, the researchers replicated the same experiments on their three-dimensional model of brain tissue. The same thing happened in it under the influence of the virus as in a conventional culture: cells began to die, the production of beta-amyloid and related proteins increased, the concentration of pro-inflammatory markers increased. In addition, the electrical activity of the cells has significantly decreased. While in the control model, neurons were able to generate and maintain impulses – the main criterion for the fact that the nerve tissue is functional – after infection with the virus, the number of impulses decreased three times, which corresponds to the ideas of neurodegeneration in the brain of people with Alzheimer's disease.
Thus, the scientists were able to reproduce on their model many pathological signs that were previously found only in the brains of patients with Alzheimer's disease, including gliosis, cell fusion and a decrease in the number of impulses. However, the authors of the work do not yet dare to speak unequivocally about the causal relationship between infection with herpes and the development of pathology. Nevertheless, the fact that even the culture medium of infected cells has an effect on neurons suggests that it is not only the aggregation of beta-amyloid on the surface of viral particles, and the relationship between herpes and Alzheimer's disease is much more complicated.
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