The new findings, published online in the journal Neurobiology of Aging, add some scientific heft to the idea, long suspected by some scientists, that herpes somehow plays a role in bringing about Alzheimer's disease.
The work links a form of the ApoE gene known as ApoE-4, which after advanced age is the leading known risk factor for getting Alzheimer's disease, with the form of herpes – herpes simplex 1 or HSV – that infects more than 80 percent of Americans and causes cold sores around the mouth. The findings from a group at the University of Rochester Medical Center show that the particular form of the gene that puts people at risk also creates a fertile environment for herpes in the brain, allowing the virus to be more active than other forms of the ApoE gene permit.
Scientists have known for more than 15 years that the ApoE-4 gene is a player in Alzheimer's disease, but the idea that it works in concert with the herpes virus is new.
"This work raises the question whether herpes in concert with ApoE-4 increases the risk of Alzheimer's disease. The data suggests that ApoE-4 may support the ability of HSV to be a more virulent pathogen," said Howard Federoff, M.D., Ph.D., the leader of the team and professor of Neurology, Medicine, and Microbiology & Immunology. He worked closely with post-doctoral research associate Renee Miller, Ph.D., on the project.
The findings, which are based on measurements of the activity levels of the herpes virus in the brains of mice with different forms of the human ApoE gene, bring together several lines of research that have pointed toward a possible role for herpes in Alzheimer's disease.
Ruth Itzhaki of the University of Manchester has led the way with several studies showing a correlation between herpes and Alzheimer's. She has shown that Alzheimer's patients who have the ApoE-4 form of the gene have more herpes DNA in the brain regions that are affected by Alzheimer's, compared to Alzheimer's patients who also have herpes but who have a different form of the ApoE gene. And she has shown that people with the ApoE-4 version of the gene who are infected with herpes are more likely to get Alzheimer's disease than people infected with herpes who have a different form of the ApoE gene, or than people who have the ApoE-4 gene but who don't have herpes.
Other scientists have found that a herpes infection is active more often – causing the tell-tale cold sores around the mouth – in the 25 percent of people who have a copy of the ApoE-4 gene. In other words, people who are frequently troubled by cold sores are more likely to have the gene that makes them more vulnerable to Alzheimer's disease.
Cold sores that come and go are the outward sign of the two different phases of the virus's life cycle. Herpes simplex is a chronic infection that lives in a person for a lifetime, periodically flaring up in a "lytic" phase where it causes cell damage, then retreating and seeking safe harbor within the body's nerves in a "latent" phase. The virus spends most of its time in the latent phase, sequestered in cells, not active and not replicating. But occasionally, when triggered by factors like stress, fatigue, certain foods, or even sunlight, the virus becomes active, traveling from its hiding places in the nervous system to cells around the mouth, damaging cells and causing cold sores.
It was this cycle of activity and latency that Miller and Federoff focused on while looking at the brain cells of mice with different forms of the ApoE gene. They looked at four groups of mice: Some had ApoE-3, which is what the majority of people carry; some had ApoE-4, which in people makes them more likely to get Alzheimer's; some had ApoE-2, which makes people less likely to get the disease; and some had no ApoE gene at all.
The team found that the virus infiltrates brain cells about the same no matter which gene is involved. But they found that the subsequent activity level of the virus generally mirrored the disease-causing potential of the gene. They found that in animals with the ApoE-4 gene, the virus is less likely to be in the quiet, latent stage of its life cycle, suggesting it has more of an opportunity to replicate. In animals with the ApoE-2 gene, the virus was less active.
The work suggests that ApoE-4 may alter the balance between the HSV life cycle forms. It's possible that the ApoE gene works as a sort of bodyguard that tries to keep cells safe from herpes, perhaps by facilitating latency. Somehow the ApoE-2 version is extremely effective at keeping the virus at bay, while in this study, the ApoE-4 version wasn't any more effective than not having an ApoE gene at all.
The ApoE gene is well known to Alzheimer's researchers. The gene, which normally plays a role in ferrying cholesterol around the body, is associated with both the cellular tangles and amyloid plaques that are found in the brains of patients with the disease. Researchers have found several ways in which the gene might make a person vulnerable to getting a disease like Alzheimer's. In people with the ApoE-4 gene, brain cells don't seem to recover as well from injury, and the cells don't form new connections as well as cells equipped with either ApoE-2 or ApoE-3. Other scientists have shown that the gene plays a role in clearing toxic amyloid beta from the brain.
"Just how ApoE-4 makes people vulnerable to Alzheimer's disease isn't resolved at all," said Federoff, who is director of the University's Center for Aging and Developmental Biology. "It may be that it works in multiple ways."
The team is exploring different ways that herpes might affect the development of Alzheimer's disease. In one study the team looking at the role of Nectin-1, a cell adhesion molecule that herpes uses as one route to infect a cell. Nectin-1 plays a crucial role in forming synapses, the structures between brain cells that move information and signals from one cell to the next. The team is studying whether herpes somehow disturbs the receptor, possibly altering the structure and function of the synapse. Damage to synapses is one of the earliest signs of Alzheimer's disease.
Another possibility is that the body's immune response against herpes somehow damages the brain, and that such damage is worse in people with the ApoE-4 copy of the gene. Earlier this year Federoff's team published a study that showed inflammation is the earliest change that could be detected in a brain affected by Alzheimer's disease, before any of the hallmark plaques or tangles and certainly long before any behavioral changes are seen. Such inflammation often is a byproduct when the immune system fights an infection.
Tom Rickey | EurekAlert!
Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory
How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy