Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice

by Giovanna De Chiara, Roberto Piacentini, Marco Fabiani, Alessia Mastrodonato, Maria Elena Marcocci, Dolores Limongi, Giorgia Napoletani, Virginia Protto, Paolo Coluccio, Ignacio Celestino, Domenica Donatella Li Puma, Claudio Grassi, Anna Teresa Palamara

Herpes simplex virus type 1 (HSV-1) is a DNA neurotropic virus, usually establishing latent infections in the trigeminal ganglia followed by periodic reactivations. Although numerous findings suggested potential links between HSV-1 and Alzheimer’s disease (AD), a causal relation has not been demonstrated yet. Hence, we set up a model of recurrent HSV-1 infection in mice undergoing repeated cycles of viral reactivation. By virological and molecular analyses we found: i) HSV-1 spreading and replication in different brain regions after thermal stress-induced virus reactivations; ii) accumulation of AD hallmarks including amyloid-β protein, tau hyperphosphorylation, and neuroinflammation markers (astrogliosis, IL-1β and IL-6). Remarkably, the progressive accumulation of AD molecular biomarkers in neocortex and hippocampus of HSV-1 infected mice, triggered by repeated virus reactivations, correlated with increasing cognitive deficits becoming irreversible after seven cycles of reactivation. Collectively, our findings provide evidence that mild and recurrent HSV-1 infections in the central nervous system produce an AD-like phenotype and suggest that they are a risk factor for AD.