Determination of the effects of Herpes simplex glycoprotein B on epigenetic alterations in in vitro models of Alzheimer's disease

Abstract

Background

Epigenetic dysregulation is increasingly recognized as a key mechanism in the development and progression of Alzheimer's disease (AD). Herpes simplex virus type 1 (HSV-1) infection has been proposed as a potential biological trigger that may accelerate neurodegeneration through epigenetic modifications. Among HSV-1 structural proteins, glycoprotein B (HSV-gB) may influence host–virus interactions affecting neuronal gene regulation.

Objective

This study aimed to investigate the contribution of HSV-gB to AD-related epigenetic alterations and to determine whether HSV-gB exposure exacerbates epigenetic dysregulation in two in vitro neuronal AD models.

Methods

Human SH-SY5Y neuroblastoma cells were used to establish two AD models: a differentiation-based aging model induced by retinoic acid and brain-derived neurotrophic factor (RA + BDNF), and an amyloid aggregation model induced by amyloid-β 1–42 (Aβ_1–42). Cells were treated with HSV-gB (190.5 pg/ml) alone or in combination with each model. Global DNA methylation, histone H3 and H4 acetylation, histone multiplex modifications, and HDAC3 and HDAC8 levels were analyzed using ELISA-based assays.

Results

HSV-gB exposure and RA + BDNF treatment induced global DNA hypomethylation and histone hypoacetylation, accompanied by significant increases in HDAC3 and HDAC8 levels. In contrast, the Aβ_1–42 model showed DNA hypermethylation and histone hyperacetylation, indicating distinct epigenetic profiles between differentiation-associated aging and amyloid-driven pathology.

Conclusions

HSV-gB contributes to AD-related epigenetic dysregulation and may amplify neurodegenerative mechanisms through HDAC-mediated chromatin remodeling. The findings highlight divergent epigenetic signatures in different AD models and support a potential role for viral factors in modulating AD-associated epigenetic pathways.

Graphical Abstract.

Schematic illustration summarizing the effects of herpes simplex virus type-1 glycoprotein B (HSV-gB) on epigenetic regulation in two in vitro Alzheimer's disease models. HSV-gB induces global DNA hypomethylation, histone H3/H4 hypoacetylation, and increased HDAC3/HDAC8 levels in the RA + BDNF-induced aging-like model, whereas distinct epigenetic patterns are observed in the Aβ_₁–₄₂-induced amyloid model. The graphical abstract was created by the authors based on the findings of the present study.