Epstein-barr virus and epigenetic modifications: insights into neurodegeneration and dehydroevodiamine as a neuroprotective agent

Abstract

Neurodegenerative diseases, including Alzheimer‘s, are complex disorders influenced not only by genetic and environmental factors but also by viral infections that can profoundly disrupt the brain's regulatory systems. Epstein-Barr Virus (EBV), a widely prevalent neurotropic herpesvirus, has emerged as a potential contributor to neurodegeneration through its capacity to induce chronic inflammation and epigenetic remodeling of host genes. This study investigates how EBV infection modulates the epigenetic status of critical neurological genes—such as BACE1, APP, LDLR, and GFAP—focusing on histone methylation and DNA methylation at splice sites that govern isoform expression. Using a neural tri-culture system comprising neurons, astrocytes, and microglia, we observed that EBV infection resulted in increased repressive histone marks (H3K9me3 and H3K27me3), altered DNA methylation patterns, elevated oxidative stress, and dysregulated expression of disease-associated genes and neurotrophic factors. Methylation-specific PCR (MSP) revealed hypomethylation near splice junctions in disease-relevant genes, correlating with isoform shifts that promote amyloidogenic and inflammatory responses. Western blotting further validated changes in isoform expression at the protein level. Importantly, treatment with the natural compound Dehydroevodiamine (DHE) reversed several EBV-induced epigenetic changes, restored histone balance, and attenuated disease markers, underscoring its therapeutic potential. Collectively, these findings suggest that EBV-driven epigenetic modifications may play a critical role in the initiation and progression of neurodegenerative processes and highlight the need for future research targeting viral-epigenetic interactions in the brain.