Wednesday, October 19, 2022

Covid-19 is linked to increased degradation of connections between nerve cells in a new brain model

Postdoctoral fellow Samudyata and doctoral student Susmita Malwade.
Source: Karolinska Institutet

Researchers at Karolinska Institutet have used cellular reprogramming in a new study to create human three-dimensional brain models and infected them with SARS-CoV-2. In infected models, the brain's immune cells showed an excessive elimination of connections between the nerve cells. The gene expression of these cells also mimicked changes observed in neurodegenerative diseases. The results hope to identify new treatments for cognitive symptoms after Covid-19 infection.

Several studies have reported persistent cognitive symptoms following a covid-19 infection, but the underlying mechanisms for this are still unknown. The researchers behind the study, published in the journal Molecular Psychiatry, have created from human induced pluripotent stem cells (iPS) three-dimensional models of the brain in test tubes, so-called brain organoids. The model differs from previous organoid models in that they also contain microglia - the brain's immune cells. In the infected models, microglia regulated genes involved in phagocytosis, "cell-eating," the researchers could also see how microglia contained an increased amount of proteins from brain cell connections, so-called synapses. The developed model and results of the study can help guide future efforts to address cognitive symptoms in the aftermath of COVID-19 and other neuroinvasive viral infections.

Cognitive difficulties after infection

"Interestingly, the study's results largely mimic what has recently been observed in mouse models infected with other neuroinvasive RNA viruses, such as the West Nile virus. These viruses are also linked to cognitive difficulties after the infection, and a persistent activation of microglia leading to excessive swallowing of synapses, which has also been suggested to cause these symptoms. Several studies have now also reported residual cognitive symptoms following a covid-19 infection, as well as an increased risk of being diagnosed with cognitive symptoms, "says co-authors Samudyata, postdoctoral fellow in Sellgren lab at Department of Physiology and Pharmacology at Karolinska Institutet.

Links to Parkinson's and Alzheimer's disease

Microglia is the brain's immune cells and performs important regulatory functions for neuronal circuits throughout our lifetime. One of these crucial functions is to break down unwanted synapses, a process that is believed to enhance and maintain cognitive functions. However, excessive degradation of synapses has been linked to diseases that debut early in life, such as schizophrenia, as well as neurodegenerative disorders later in life, such as Alzheimer's disease.

By sequencing genes in single cells, the authors were also able to study how different cell types in the model responded to the virus.

"Microglia showed a clear upregulation of genes stimulated by interferons, and similar largely to the pattern observed in microglia in neurodegenerative diseases such as Parkinson's and Alzheimer's disease. This signature was also observed at a later date when the viral load was almost minimal, "says co-authors Susmita Malwade, PhD student in Sellgren lab at the Department of Physiology and Pharmacology at Karolinska Institutet.

The researchers now want to study how different drugs could inhibit the changes seen in the infected models.

The study was primarily funded by the Marianne and Marcus Wallenberg Foundation, One Mind Foundation / Kaiser Permanente, the Brain Fund and the Swedish Research Council.

Source/Credit: Karolinska Institutet