Herpes virus may contribute to Alzheimer’s disease through transposition elements

Researchers at the Cleveland Clinic Genome Center outlined the pathways of human herpes simplex virus 1 (HSV1) that can be used to contribute to Alzheimer’s disease in the aging brain. In a published report Alzheimer’s Disease and Dementia: Journal of Alzheimer’s Disease Societythe researchers also shared two FDA-approved commercially available drugs, reversing this pathway in a laboratory setting.

These findings are the first concrete evidence supporting a controversial link between human herpes virus (HHV) and Alzheimer’s disease. Senior author and director of the Genome Center said that it shows the potential of herpes to cause dementia AIDS to continue working to prevent and cure neurodegenerative diseases.

For most people, herpes infection is just an inconvenience or harmless fact in life. Many herpes viruses exist alone in a large proportion of people around the world, meaning that almost everyone will shrink at least three types of herpes viruses as adults. Some of these viruses do not cause symptoms, while others only cause minor illnesses such as mono or chickenpox. However, even if these diseases subside, the infected person still carries herpes virus for the rest of his life, with only occasional minor symptoms such as cold sores.

Although herpes viruses are generally harmless to suppress, there is growing evidence that our immune system may lose its ability to suppress them. This can occur naturally as you age, pregnancy and illness. Recent research shows that as herpes viruses become more active, they can cause diseases, including pregnancy complications, birth defects, or delayed development in our children and even cancer.

Dr Cheng said it is obvious that HSV and other herpes viruses are risk factors that do not contain geriatric diseases. Indirect evidence has linked HSV-1 to Alzheimer’s disease, but there is no explanation for how these phenomena are linked.

Dr. Cheng hypothesized that potential HPV-1 infection could trigger Alzheimer’s disease by directly activating transposable elements previously associated with the progression of aging brain disease in Cheng Lab. Transposable elements are a small portion of DNA that can actively “jump out” from our chromosomes and move randomly to distant areas of our DNA. These elements reintegrate into these new regions of our genome, destroying their function of disrupting genes. Almost half of our DNA is made up of transferable elements that become more active as we age.

After mapping all the transposable elements associated with Alzheimer’s disease, the researchers analyzed four publicly available data sets containing hundreds of brain cells affected by health and Alzheimer’s disease RNA sequencing data. Cheng Lab received collaboration and helped interpret data from Jae Jung, PhD, president of infection biology; James Leverenz, MD, the Lou Ruvo Brain Health Center at the former Cleveland Clinic; and Case Western Reserve University and the University of Nevada Las Vegas collaborators.

The team identified several TEs that were more highly activated in brains containing HSV RNA than uninfected or healthy brains. They then tested HSV-1-infected brain cells to see if the identified TE was activated and the effects on neuroinflammatory and accumulation of proteins associated with Alzheimer’s disease.

The results are step-by-step guides on the link between HSV-1 and the marker of Alzheimer’s disease:

1. Individuals contract HSV-1 or their potential HSV-1 infection becomes more active due to natural outcomes of age;
2. HSV-1 is associated with transposable elements (e.g. Line 1) activation;
3. Transposable elements disrupt key genetic processes in the brain associated with the accumulation of tau and Alzheimer’s-like proteins, and;
4. The accumulated protein contributes to inflammation and neurodegenerativeness.

Investigators then used artificial intelligence to analyze 80 million publicly available patient health records to see if individuals who prescribed antiviral herpes drugs continue to receive fewer diagnoses of Alzheimer’s. The herpes drugs Valacyclovir and Acyclovir are associated with a significant reduction in Alzheimer’s disease. Treating laboratory models with these drugs seems to turn infections toward the Alzheimer’s disease pathway, mechanistically supporting what they observe in real-world patient data.

“These results further demonstrate the potential relationship between HSV-1 infection and Alzheimer’s disease and provide two potential drug candidates that may provide treatment for currently incurable diseases,” Dr Cheng said. “We hope that our findings, if widely used, could also provide new strategies to treat other neurological diseases associated with herpes virus or other viruses.”

The study was funded by the National Institute of Aging (NIA).