SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice

The study, titled “SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice,” published in Cell Reports, offers significant insights into the neurological impacts of COVID-19.

Here’s a summary:

  1. Study Objective and Method: The study aimed to understand the mechanisms behind cognitive dysfunction in post-COVID-19 syndrome, focusing on the role of the SARS-CoV-2 Spike protein. Researchers infused Spike protein directly into the brains of mice and observed behavioral changes over time​​.
  2. Key Findings:
    • Late Cognitive Impairment in Mice: Mice infused with Spike protein displayed late cognitive impairment and synapse loss, similar to post-COVID-19 syndrome in humans. This impairment was observed notably between 30 and 45 days after Spike protein infusion​​.
    • Neuroinflammation and Microglial Activation: The study found that neuroinflammation and microglial activation were involved in the Spike-induced memory dysfunction. Interestingly, neurons were not directly affected by the Spike protein, suggesting the primary role of microglia in cognitive dysfunction​​.
    • Synaptic Phagocytosis by Microglia: Spike protein infusion led to synaptic phagocytosis by microglia, mediated by the complement component C1q. Blocking C1q significantly rescued memory impairment in Spike protein-infused mice​​.
    • Role of Toll-like Receptor 4 (TLR4): TLR4 was identified as a key mediator in cognitive dysfunction induced by Spike protein. Inhibition of TLR4, both genetically and pharmacologically, protected against memory dysfunction and synaptic pruning caused by Spike protein​​.
    • Human Genetic Association: In a cohort of 86 COVID-19 patients, a specific SNP (rs10759931) in the TLR4 gene was associated with an increased risk of cognitive impairment after COVID-19. Individuals with the GG genotype of this SNP showed a higher risk for developing cognitive dysfunction following SARS-CoV-2 infection​​.
  3. Significance and Implications: This research provides a deep understanding of how SARS-CoV-2 can lead to long-term cognitive issues, highlighting the central role of TLR4 and the complement system in mediating these effects. It underscores the importance of further exploring TLR4 as a potential therapeutic target for addressing long-term cognitive dysfunctions associated with COVID-19.

This study contributes valuable knowledge about the neurological consequences of COVID-19 and emphasizes the need for continued research into the long-term effects of COVID-19 on brain health, particularly in genetically susceptible individuals.

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