Herpes Simplex Virus-1 Proteins Drive Alzheimer’s Disease Pathologies in Humans

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. Methods 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. Results 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 introduced HSV-1 in human derived brain organoids and imaged the relationships between viral proteins and the formation of AD pathologies via expansion microscopy. We found that HSV-1 infection triggered these pathologies, pointing out that viruses may be triggers of immune responses driving AD. Conclusions this study sheds light on one common pathogen, HSV-1, while serving as a framework to unveiling molecular causation between infectious agents and AD hallmarks.