SARS‐CoV2 Nucleocapsid Protein induces Tau pathological changes in the mouse hippocampus

Abstract

AbstractBackgroundNeurologic manifestations are emerging as an immediate consequence of SARS‐CoV2 infection, the etiologic agent of COVID19. Although little is known about the long‐term consequences of SARS‐CoV2 infection, there is the possibility that infection may trigger long‐term neurological effects. Exposure to pathogens in fact triggers inflammation in the brain and exacerbates Tau pathological changes in animal models of Alzheimer disease. Reports of the presence of SARS‐CoV2 in the brains of subjects with COVID19 are emerging and a study in brain organoids revealed that SARS‐CoV2 alters the phosphorylation and distribution of Tau in infected neurons, but the mechanisms are currently unknown. We hypothesize that these pathological changes are due to recruitment of Tau into stress granules (SG) operated by the Nucleocapsid protein (NP) of SARS‐CoV2.MethodTo address whether exposure to SARS‐CoV2 may predispose to develop dementia, we investigated whether NP interacts with Tau and induces hyperphosphorylation and aggregation of Tau in human iPSC cells and hippocampal neurons in vivo. We tested whether NP interacts with Tau by co‐immunoprecipitation experiments. Mechanistically, we tested whether posttranslational modification of NP and Tau by SUMO2 modulates their distribution in SG and their pathological interaction. We expressed NP for 2 months, with or without SUMO2, in the hippocampus of 6 months old wild type and JNPL3 mice, before performing Y‐maze. After behavioral assessment, the mice were sacrificed and brains were isolated to perform biochemical and immunofluorescence analyses.ResultWe found that NP and Tau co‐localize and physically interact in human cells. We also found that NP induces hyperphosphorylation of Tau and reduces the amount of synaptic proteins in neurons. This is also paralleled by a reduction in the cognitive abilities of mice infected with NP in their hippocampus. Finally we found that modulation of SUMOylation dramatically affects SG induced by NP in cells, Tau hyperphoshorylation, as well as cognitive performance in mice infected with NP.ConclusionOur data demonstrate that NP induces pathological changes in cells and animals expressing wild type Tau, and aggravates the pathology in neurons expressing mutant forms of Tau, both in vitro and in vivo. Moreover we demonstrate that SUMO2 conjugation ameliorates NP‐induced Tau pathology.