Using brain ‘organoids’, researchers at Karolinska Institutet have found that COVID infection results in damage from immune cells and gene expressions similar to those found in neurodegenerative disorders. Their findings were published in Molecular Psychiatry.
The findings could help to identify new treatments against persistent cognitive symptoms after a COVID infection.
Neurological symptoms in ‘long COVID’ have been widely reported but the underlying mechanisms for this remains unknown. To find out, the study’s researchers created brain organoids from human induced pluripotent stem (iPS) cells. The model differs from previous organoid models as the researchers also included the brain immune cells – microglia – in the model. In the infected models, microglia excessively engulfed synaptic structures and displayed upregulation of factors involved in phagocytosis. The developed model and the findings in the study could help to guide future efforts to target cognitive symptoms in the aftermath of COVID and other neuroinvasive viral infections.
Post-infection cognitive deficits
“Interestingly, our results to a large extent 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 residual cognitive deficits after the infection, and a persisting activation of microglia leading to an excessive engulfment of synapses, which has been suggested to drive these symptoms. Multiple studies have now also reported remaining cognitive symptoms after a COVID infection, as well as an increased risk of receiving a diagnosis of a disorder characterised by cognitive symptoms,” says co-first author of the study Samudyata, a postdoctoral fellow at Karolinska Institutet.
Connections to Parkinson’s and Alzheimer’s disease
Microglia also carry out important regulatory functions of the neuronal circuitries in the brain, one of which is engulfing unwanted synapses, a process that is believed to improve and maintain cognitive functions. However, excessive engulfment of synapses has been linked to both neurodevelopmental disorders, such as schizophrenia, as well as to neurodegenerative disorders including Alzheimer’s disease.
By sequencing genes in single cells, the authors could also study how different cell types in the model responded to the virus.
“Microglia displayed a distinct gene signature largely characterized by an upregulation of interferon-responsive genes, and included pathways previously linked to neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease. This signature was also observed at a later time-point when the virus load was minimal,” says co-author of the study Susmita Malwade, a doctoral student at Karolinska Institutet.
The researchers will now study how different pharmacological approaches can reverse the observed changes in the infected models.
Source: Karolinska Institutet
