ScholarWorks@성균관대학교

초록

Neurodegenerative symptoms have been reported in COVID19 patients. How SARS-CoV-2 virus contributes to neurodegenerative pathogenesis and the interactions with central immunity, however, remains unclear, partly due to lack of clinically relevant human brain models recapitulating the neuron-glial crosstalk. Here, we investigated the contribution of SARS-CoV-2 Spike 1 (S1) on neurodegeneration using tri-cultures of human neurons, microglia, and astrocytes. In neuron-astrocyte culture derived from human neural progenitor cells, S1 induced the reactive astrocytes, synaptic loss, accumulation of hyperphosphorylated tau, alpha-synuclein, and neurodegeneration. S1 triggered both pathological tau and alpha-synuclein neurons via TANK-binding kinase 1 (TBK1) and suppressed interferon type I (IFN-I) signaling (including IRF3 and IFN-beta) while activating nuclear factor kappa-light-chain-enhancer of activated B (NF-kappa B). In single-cultured astrocytes, we found that S1 activated both IFN-I signaling and NF-kappa B, leading to IFN-beta and induced nitric oxide synthase (iNOS) production; inducing detrimental neuroinflammation and tau phosphorylation observed in the co-culture models of neurons derived from SH-SY5Y and human astrocytes. Interestingly, S1 induced a microglial neuroprotective neuroinflammation via TBK1 signaling, which attenuated both tau and alpha-synuclein pathology validated in the tri-culture. Taken together, our study has unraveled the multi-scale roles of viral protein in the brain and the dual TBK1 signaling as the potential therapeutic targets for viral infection-mediated neurodegeneration.

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