Researchers identified the TLR4 receptor as a potential target for treating COVID-related memory loss

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Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA.

Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion.

Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.

In a study published in the Journal of Neuroscience in January 2021, researchers identified the TLR4 receptor as a potential target for treating COVID-related memory loss. TLR4 is a protein that is part of the immune system and is found on the surface of cells in the brain, as well as in other organs.

The study involved analyzing brain tissue from mice infected with a virus that is similar to SARS-CoV-2 and from human patients who had died from COVID-19. The researchers found that the virus activated the TLR4 receptor, which triggered an immune response in the brain. This immune response caused inflammation and damage to the brain cells, which led to cognitive impairment and memory loss.

The researchers then tested a drug called TAK-242, which blocks the TLR4 receptor, in mice infected with the virus. They found that the drug reduced inflammation in the brain and improved the mice’s cognitive function.

The researchers also looked at brain scans from COVID-19 patients who had recovered from the acute phase of the disease. They found that these patients had reduced gray matter in areas of the brain that are involved in memory and cognitive function. This suggests that the virus can cause long-term damage to the brain even after the acute phase of the disease has passed.

The study’s findings suggest that TLR4 inhibition may be a promising strategy for treating COVID-related cognitive impairment and memory loss. However, more research is needed to determine the safety and efficacy of TLR4 inhibitors in humans.

A new research has found that :

  • Spike protein infusion into mouse brain induces late cognitive dysfunction
  • Spike protein induces late hippocampal microgliosis and synapse loss
  • Blockage of TLR4 renders mice resistant to Spike-induced cognitive dysfunction
  • TLR4-2604G>A GG genotype was related to poor cognitive outcome in COVID-19 patients

referenc link : https://www.cell.com/cell-reports/fulltext/S2211-1247(23)00200-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124723002000%3Fshowall%3Dtrue#secsectitle0075

Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA.

Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion.

Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.

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