Sub-Productive Expression of Herpes Simplex Virus-1 proteins as a Driver for Alzheimer's Disease Pathologies

DNA and RNA of Herpes Simplex Virus 1 (HSV-1) were found in the brains and serological samples of Alzheimer’s disease (AD) patients. Such molecular presence of HSV-1 in AD patients is especially intriguing as HSV-1 virions are rarely detected in AD brains. To follow the molecular footsteps detected, we imaged viral proteins in postmortem human AD brains at superior resolution using expansion microscopy, a tissue manipulation method that physically expands the samples by a factor of 4.5x, allowing a 40 nm imaging resolution, and immunolabeled herpetic proteins, AD pathologies and cell markers. Protein levels previously undetectable with standard methods, i.e., immediate-early herpetic protein were found across large brain areas, while late proteins of HSV-1 were not detected. Importantly, we found that HSV-1 immediate early proteins strongly co-localized with AD pathologies. Consequently, we hypothesized that expression of HSV-1 proteins during latency may be linked to AD pathology. We are now characterizing the HSV-1 proteome in AD brains by imaging key latent and non-latent proteins in expanded AD brain slices and examining their colocalization with AD pathologies across brain areas and disease stages. Finally, we are inducing HSV-1 latency in human brain organoids and imaging the relationships between viral proteins and the formation of AD pathologies via expansion microscopy. Pathogens may be triggers of immune responses driving AD; this study would shed light on one common pathogen, HSV-1, while serving as a framework to unveiling molecular causation between infectious agents and AD hallmarks.