Legrand, A.; Boluda, S.; Boukhvalova, M.; Rozenberg, F.; Bottlaender, M.; Lagarde, J.; Sarazin, M.; Helmer, C.; Linard, M.; Delatour, B.

Herpes Simplex virus type 1 (HSV-1) is a highly prevalent neurotropic virus from the alphaherpesviruses family. In recent years, a growing body of research has focused on the potential role of HSV-1 infections and recurrent reactivations in the pathophysiology of Alzheimer's disease (AD). In particular, it has been hypothesized that HSV-1 could initiate or amplify the formation of neuropathological lesions characteristic of AD. To explore further this hypothesis, we adopted an integrated approach aiming at deciphering the impact of HSV-1 infection on AD molecular markers (A-beta and Tau pathologies) and combining experimental animal models of in vivo infection, postmortem neuropathological analysis of AD brains, as well as in-vivo clinical analysis in AD patients. In animal models of peripheral (labial) infection with HSV-1 virus, we analyzed viral dissemination from peripheral tissues to the CNS, and the associated neuropathological consequences. Histological and molecular analyses revealed the occurrence of viral material (RNA, proteins) in the brainstem, the primary site of viral neuroinvasion, and in more anterior regions of the brain. Viral signatures were accompanied by early abnormal deposits of A-beta peptides and accumulation of phosphoTau (pTau) proteins in various brain areas. Neuropathological examination of AD/control participants also underlined the presence of HSV-1 DNA in the human brainstem (pons) that was always associated with local A-beta/Tau aggregates. Finally, in AD patients, associations were found between HSV-1 seropositivity and neuropathological lesion burden (region-specific Tau and A{beta} deposition detected by neuroimaging). Taken together, these data provide new evidence in favor of the involvement of HSV-1 in the pathophysiology of AD, stressing a possible causal link between HSV-1 infection, neuroinvasion and AD neuropathological hallmarks (A-beta lesions and tauopathy).