Studies have suggested that viruses may play a role in certain neurodegenerative diseases. Some of these studies have linked the herpes simplex virus-1 (HSV-1) and Alzheimer’s disease. The herpes simplex virus type can affect the brain in a number of ways including encephalitis, chronic inflammation, and the brain region function. Now, a new study by researchers at the University of Pittsburgh adds more evidence to the link between Alzheimer’s disease and HSV-1. Their new research has also revealed how tau protein may initially protect the brain from the virus but later contributes to brain damage.
The findings are published in Cell Reports in an article titled, “Anti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer’s disease,” and led by Or Shemesh, PhD, assistant professor in the department of ophthalmology at Pittsburgh University.
“Alzheimer’s disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau),” the researchers wrote. “Emerging evidence suggests a potential link between AD pathologies and infectious agents, with herpes simplex virus 1 (HSV-1) being a leading candidate.”
The researchers used metagenomics, mass spectrometry, western blotting, and decrowding expansion pathology to detect HSV-1-associated proteins in human brain samples. “Expression of the herpesvirus protein ICP27 increases with AD severity and strongly colocalizes with p-tau but not with Aβ,” the researchers noted. “Modeling in human brain organoids shows that HSV-1 infection elevates tau phosphorylation.”
The researchers identified forms of HSV-1-related proteins in Alzheimer’s brain samples, with greater amounts of viral proteins co-localized with tangles of phosphorylated tau—one of the hallmarks of Alzheimer’s disease pathology—in brain regions especially vulnerable to Alzheimer’s across disease stages.
Further studies on miniature models of human brains in a Petri dish suggested that HSV-1 infection could modulate levels of brain tau protein and regulate its function, a protective mechanism that seemed to decrease post-infection death of human neurons.
“Our study challenges the conventional view of tau as solely harmful, showing that it may initially act as part of the brain’s immune defense,” said Shemesh. “These findings emphasize the complex interplay between infections, immune responses, and neurodegeneration, offering a fresh perspective and potential new targets for therapeutic development.”
While the precise mechanisms by which HSV-1 influences tau protein and contributes to Alzheimer’s disease are still unknown, Shemesh and his colleagues plan to explore those questions in future research. They aim to test potential therapeutic strategies that target viral proteins or fine-tune the brain’s immune response and investigate whether similar mechanisms are involved in other neurodegenerative diseases, such as Parkinson’s disease and ALS.
