Zika virus infection induces a persistent accumulation of Alzheimer's disease-like Tau phosphorylation in adult immunocompetent mice in association with memory and social behavior impairments.

Abstract

Clinical and epidemiological data support the link between viral encephalitis and neurodegeneration but its causal mechanism remains mostly unknown. Zika virus (ZIKV) is an emerging, neurotropic flavivirus susceptible to induce cognitive impairments in infected adults. In this work we have analyzed the capacity of ZIKV to induce the accumulation of pathological phosphorylated Tau protein (pTau), a major driver of neurodegenerative disorders such as Alzheimer's disease, throughout the infection of adult immunocompetent mice. The capacity of ZIKV to induce pTau in vivo, was analyzed in the long term in three Collaborative Cross mouse strains displaying different responses to ZIKV. The establishment and propagation of pTau was quantified up to 60 days post-infection (dpi) in correlation with the level and localization of neuronal viral infection and of microglia activation using immunofluorescence, immunohistochemistry, wide field and confocal microscopy and gene expression analysis. Strength, coordination, memory and social behavior were evaluated before and following the establishment and progression of pTau. The role of microglia on ZIKV-induced pTau was investigated by partially depleting microglial cells using PLX3397 (PLX). ZIKV infection induced a significant accumulation of pTau starting at 15 that persisted at least until 60 dpi. At 15 dpi, pTau was observed in ZIKV-infected neurons in the CA2 and CA1 regions of the hippocampus and in non-infected cortical neurons in association with neuroinflammation and social behavior alterations. At 30 dpi, pTau progressed independently of infection and inflammation, positively correlated to PLX-susceptible Apoe gene expression in association with short-term memory defects. These results shed light on how brain viral infections, which are a major concern for public health, drive pTau accumulation and propagation in link with memory impairment and social behavior alterations laying the groundwork for potential new therapeutic treatments.