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<p>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-β) while activating nuclear factor kappa-light-chain-enhancer of activated B (NF-κB). In single-cultured astrocytes, we found that S1 activated both IFN-I signaling and NF-κB, leading to IFN-β 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.</p> Graphical Abstract <p></p>

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SARS-CoV-2 S1-Inducing Reactive Astrocyte and Proteinopathies via TANK-Binding Kinase 1 in Human Neuroglia Model

  • 期刊论文

  • 发表日期：

    2025年7月15日

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  • Huyen Ngo,
  • You Jung Kang,
  • Yen N. Diep,
  • Van Thi Ai Tran,
  • Sein Kim,
  • Sungsu Park,
  • Luke P. Lee,
  • Hansang Cho

摘要

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-β) while activating nuclear factor kappa-light-chain-enhancer of activated B (NF-κB). In single-cultured astrocytes, we found that S1 activated both IFN-I signaling and NF-κB, leading to IFN-β 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.

Graphical Abstract