One of the distinctive features of Alzheimer’s disease (AD) is the accumulation of a group of insoluble protein fibrils (Amyloid-β peptide fibrilization) as β-amyloid plaques . In the past, scientists thought that amyloid-β peptide (Aβ) was just a useless secondary product of biochemical pathways that was eventually eliminated in healthy cells. This assumption, however, was inconsistent when considering the high genetic conservation of Aβ across different species. Recently, researchers have discovered that this apparently annoying protein is not as worthless as it was once thought. In fact, Aβ seems to be an immune system super hero that fights against the bad guys in our body. Formally speaking, Aβ is an antimicrobial peptide (AMP) that starts to agglutinate (Aβ oligomerization) when it detects certain pathogens. As a result of the Aβ deposition in cells, the brain has a neuroinflammatory response. Apparently, this immune response leads to neural death in order to prevent the infection from spreading to other brain regions. Aβ oligomerization can end up protecting our brain if the neuroinflammatory response is controlled, otherwise, the accumulation of Aβ oligomers will lead to more neuronal death, which is the underlying pathology for multiple human diseases, including Alzheimer’s disease.
You are probably wondering now what the relevance of the herpes viruses is in this story. Let me begin by saying that all of us have at least a herpes virus. Yes, herpes, which in Greek means “to creep” but don’t freak out! Genital herpes is not the only type of herpes virus. There are multiple herpes viruses and they are known as the herpesviridae family. Nine herpes viruses affect humans and five of them are present in around 90% of the human population. In the case of Alzherimer’s disease, herpes simplex virus 1 (HSV1) has been shown to be correlated to an increase in Aβ deposition. This is why a group of scientists in Harvard decided to explore the question of whether Aβ oligomerization in the brain had a protective role against herpes virus infection.
To answer this question, the researchers investigated three herpes viruses (HSV1, HHV6A, and HHV6B, the latter two standing for human herpesvirus 6A and 6B, respectively) in vivo and in vitro. For the in vivo experiments, they used a transgenic mouse model used in AD research known as 5XFAD. These animals have high levels of Aβ protein in their first weeks of life, which allows the researchers to explore whether more Aβ protein can protect the brain from herpes virus infection. They injected wild type (WT) and 5XFAD mice’s brains with a high dose of HSV1 only (no HHV6A/B were used because mice lack homologous receptors for these human viruses in their neurons). Subsequently, the researchers observed how long it took mice to die. Of course, the researchers had a control group of mice that went through surgery but did not get a lethal injection of HSV1. The results indicated that 5XFAD had a higher survival rate than WT animals (see fig.1). This increase in survival rate was, presumably, due to the protective effects of Aβ protein against HSV1 in 5XFAD mice.
The next piece of evidence that supports the interpretation of this result was the examination of brain sections from 5XFAD and WT mice that were infected with HSV1. The authors used antibodies to visualize the location of HSV1 and Aβ protein in the hippocampus of these mice. The results showed that HSV1 and Aβ were co-localized in the brain of 5XFAD (see fig.2). More specifically, the presence of Aβ proteins in 5XFAD brains led to agglutination of Aβ around the herpes virus, apparently as a form of protection against viral infection.
The in vitro experiments were in line with the findings in vivo. The researchers found that those cell cultures where Aβ protein was expressed showed a lower percent of infection by HSV1 than those where Aβ was eliminated (immunodepleted: reducing a protein by means of antibodies). Similarly, the authors performed transmission electron micrographs (TEMs which is a very powerful form of microscopy) and found that cells infected with HSV1, HHV6A, or HHV6B, and expressing Aβ protein presented fibrilization(the formation of protein fibers) around the virus (see Fig. 3).
Taken together, these results suggest that Aβ protein might have a protective role against herpes viruses in the brain. These findings do not directly demonstrate a relationship between AD and herpes virus, but they are strong evidence that Aβ protein oligomerization can be triggered by pathogens such as herpes virus. Because this is one of the major underlying pathologies of Alzheimer’s disease, it is logical to think that the exposure of the brain to herpes virus might lead to a higher risk of developing AD. As we get older, the brain blood barrier (our friendly bouncer of undesired substances in the brain) gets leaky, so our brain gets exposed to a wider set of substances, including pathogens. It is possible that this is one of the events triggering Aβ protein agglutination in aging populations because herpes viruses are now able to move from the peripheral system to the central nervous system.
For more information:
Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, Gyorgy B, Breakefield XO, Tanzi RE, Moir RD (2018)Alzheimer’s Disease-Associated beta-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection. Neuron 99:56-63 e53.