New research from scientists at Cleveland Clinic’s Genome Center and their collaborators at other institutions describes a pathway that human herpes simplex-1 (HSV-1) can use to contribute to the development of Alzheimer’s disease. They have also identified two FDA-approved drugs that successfully reversed the pathway in the lab. Full details are published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association in a paper titled, “Human herpesvirus-associated transposable element activation in human aging brains with Alzheimer’s disease.”
Feixiong Cheng, PhD, Genome Center director and senior author on the study, claims that their findings provide concrete evidence of a possible link between human herpesviruses and Alzheimer’s disease. Many people around the world are either currently infected or will contract herpesviruses by adulthood. Some infections are asymptomatic while others cause minor illnesses. However, even after the illnesses subside, infected individuals carry the virus for the rest of their lives.
While herpesviruses are generally harmless when they are suppressed, there is evidence that shows that immune systems can lose the ability to suppress them under certain conditions including as people age. Circumstantial evidence from other studies has linked HSV-1 to Alzheimer’s disease, but the exact mechanism was not known.
Cheng and his team hypothesized that latent HPV-1 infections could trigger Alzheimer’s disease by directly activating the transposable elements that they had previously connected to disease progression in aging brains. Transposable elements are small pieces of DNA that can physically “jump” out of chromosomes and randomly move to far-away regions of our DNA.
They identified several transposable elements that were more highly activated in Alzheimer’s-affected brains containing HSV RNA, compared to uninfected or healthy brains. They then tested HSV-1 infected brain cells to see whether the identified transposable elements were activated. They also assessed any effects on neuroinflammation and protein accumulation, which are associated with Alzheimer’s disease.
What they found was that when people either contract HSV-1 or when latent infections become active with age, the infection is linked with the activation of transposable elements like LINE-1. Once these are activated, they disrupt important genetic processes in the brain that are associated with the accumulation of Tau and other Alzheimer’s-linked proteins which contribute to inflammation and neurodegeneration in the brain.
Next, the scientists analyzed publicly available health records to see if people who were prescribed antiviral herpes medications were less likely to be diagnosed with Alzheimer’s later in life. They found evidence suggesting that two herpes medications, valacyclovir and acyclovir, were associated with significantly reduced instances of Alzheimer’s disease. When they tested the drugs in virus-infected human brain organoid models, they seemed to successfully reverse the activation of transposable elements that impact the Alzheimer’s disease pathway.
Commenting on the study, Cheng noted that their findings could open a door to “new strategies for treating other neurological diseases associated with herpesviruses or other viruses.”