ABSTRACT Herpes simplex virus type I (HSV-1) infection is a potential risk factor involved in the pathogenesis of Alzheimer’s disease (AD) and contributes to the AD viral hypothesis. However, further understanding of the neuropathological effects of the HSV-1 infection is hampered by the limitations of existing infection models due to the distinct differences between human brains and other mammalians’ brains. Here we generated cerebral organoid models derived from pluripotent stem cells to investigate the HSV-induced pathogenesis associated with AD and the role of antiviral drugs in the phenotypic rescue. Our results identified that the HSV-1-infected cerebral organoids recapitulated multiscale neuropathology pertaining to the onset and progression of AD across the genetic, cellular, and tissue levels, including the multicellular Aβ deposition, dysregulated endogenous AD mediators, reactive gliosis, neuroinflammation, and neural loss. Furthermore, we identified that two antiviral drugs, namely Ribavirin (RBV) and Valacyclovir (VCV), inhibited HSV-1 replication and rescued the neuropathological phenotypes associated with AD in the HSV-1-infected cerebral organoids, implying their therapeutic potential to slow down the progression of AD. Our study provides a high-fidelity human-relevant in-vitro HSV-1 infection model to reconstitute the multiscale neuropathological features associated with AD and discover therapeutic drug candidates relevant to the AD viral hypothesis. IMPORTANCE AD is a progressive neurodegenerative disorder characterized by neuronal death, brain atrophy, and cognitive impairment. HSV-1 is a neurotropic double-stranded DNA virus resulting in long-term neurological sequelae in adults. There is accumulating evidence indicating that AD may be associated with HSV-1 infections. In this study, we generated human-physiologically related cerebral organoids derived from human embryonic stem cells (hESCs) to investigate the influence of HSV-1 infection on the neuropathology associated with AD. We found that the HSV-1-infected cerebral organoids could model typical neuropathological features associated with AD. Additionally, we discovered that both RBV and VCV significantly rescued the HSV-1-induced pathological phenotypes associated with AD. These findings may open new avenues of consideration related to HSV-1 infection and AD. Furthermore, the contribution of these antiviral drugs to AD linked to HSV-1 infection will provide new clues to potential new therapies.

Cerebral organoids for modeling of HSV-1-induced-multiscale neuropathology associated with Alzheimer’s disease and phenotypic rescue