Sex-Specific Mechanisms of HSV-1 and EBV in Alzheimer’s Disease Risk
Viral infections, particularly members of the Herpesviridae family, have been associated with an increased risk of Alzheimer’s disease (AD). While research into the microbial pathogenesis of AD has identified mechanisms through which various viruses can modulate AD processes, critical questions remain unanswered: Can all these viruses contribute to AD development, and under what specific conditions each virus can contribute to AD development? Given that these viruses are widespread in the general population, why do some individuals develop AD while others remain resilient? Importantly, women face double the risk of developing AD compared to men, raising a crucial question: how do viral infections differentially affect women compared to men? This project employs an integrative approach combining in vivo experimental methods and systems bioinformatics to address these questions. We aim to investigate how Herpes Simplex Virus Type 1 (HSV-1) and Epstein-Barr virus (EBV), in combination with genetic predispositions (APOE variants), influence sex-specific AD susceptibility using transgenic mouse models. Our study will incorporate brain region-specific transcriptomic analyses, neuropathological assessments, and cognitive tests to determine how these factors interact to alter sex-specific AD risk. Additionally, using gonadectomized male and female APOE4 transgenic mice infected with EBV, we will examine how the absence of sex hormones (estrogen and testosterone) affects viral-mediated neuropathology and cognitive outcomes. For the first time, our studies will provide critical insights into how HSV-1 and EBV drive AD under specific genetic and hormonal conditions, laying the foundation for personalized, sex-specific therapeutic strategies for AD and enabling targeted prevention and treatment approaches.