HSV-1 infection induces phosphorylated tau propagation among neurons via extracellular vesicles

Extracellular vesicles (EV), key players in cell-to-cell communication, maycontribute to disease propagation in several neurodegenerative diseases, includingAlzheimer’s disease (AD), by favoring the dissemination of neurotoxic proteins withinthe brain. Interestingly, growing evidence supports the role of herpes simplex virus type1 (HSV-1) infection in the pathogenesis of AD. Here, we investigated whether HSV-1infection could promote the spread of phosphorylated tau (ptau) among neurons viaEV. We analyzed the ptau species that were secreted via EV following HSV-1 infectionin neuroblastoma cells and primary neurons, focusing particularly on T205, T181, andT217, the phosphorylation sites mainly associated with AD. Moreover, by overexpressinghuman tau tagged with GFP (htauGFP), we found that recipient tau knockout (KO) neuronsuptook EV that are loaded with HSV-1-induced phtauGFP. Finally, we exploited an in vivomodel of acute infection and assessed that cerebral HSV-1 infection promotes the releaseof ptau via EV in the brain of infected mice. Overall, our data suggest that, followingHSV-1 infection, EV play a role in tau spreading within the brain, thus contributing to neurodegeneration.