Potential Involvement of Varicella Zoster Virus in Alzheimer’s Disease/Dementia via Reactivation of Herpes Simplex Virus Type 1

Abstract Background Infections are associated with cognitive decline and development of AD/dementia. Epidemiological studies have revealed an increased AD/dementia risk after shingles, caused by varicella zoster virus (VZV), and/or a decreased risk after vaccination against shingles. This suggests that VZV might reside latently in brain, and on reactivation might cause direct damage in brain, as is thought to be the case with herpes simplex virus type 1 (HSV1), a virus strongly implicated in AD. Alternatively, shingles‐induced inflammation could lead to neuroinflammation and reactivation of HSV1 in brain, i.e., to an indirect consequence – a suggestion previously made to account for the risk of AD/dementia conferred by infections (Itzhak i and Dobson 2002), and for the reduction in risk after certain vaccinations ‐ by preventing occurrence of infection and consequent reactivation. Our aim was to investigate these possibilities by infecting cell cultures with VZV. Method Experiments were carried out infecting human‐induced neural stem cells (hiNSC) cultures, and cultures quiescently infected with HSV1 with VZV. Cultures were observed for the presence of AD‐related phenotypes such as beta amyloid and P‐tau accumulation, gliosis, and neuroinflammation. Result Cells infected with VZV do not show the main AD characteristics ‐ beta amyloid and P‐tau accumulation – which HSV1 does cause ‐ but do show gliosis and increased levels of several cytokines, suggesting that VZV’s action is indirect. However, very intriguingly, we found that VZV infection of cells quiescently infected with HSV1 leads to reactivation of HSV1 and consequent AD‐like changes, including beta amyloid and P‐tau accumulation, supporting the above infection‐reactivation concept. Conclusion Our results support a role for VZV in AD/dementia via reactivation of HSV1 in brain and in combination with some current preliminary results, indicate that the risk of cognitive decline and of dementia conferred by some infectious diseases might indeed result from their causing HSV1 reactivation in brain.