Herpes Simplex Virus-1 Proteins as Drivers for Alzheimer’s Disease Pathologies

Abstract Background 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. Method 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. Result We found an abundance of herpetic proteins, previously undetectable with standard methods, across large brain areas. Importantly, we found that HSV-1 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 in the process of characterizing the HSV-1 proteome in AD brains by imaging key proteins in expanded AD brain slices and examining their colocalization with AD pathologies across brain areas and disease stages. As a complementary system to the fixed human brain slices, we are exposing live human brain organoids, to HSV-1, and imaging the relationships between viral proteins and the formation of AD pathologies via expansion microscopy. Conclusion 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.