Some viral diseases could possibly contribute to neurodegeneration. This is reported by researchers of the DZNE in the journal "Nature Communications". Their assessment is based on laboratory experiments in which they were able to show that certain viral molecules promote the intercellular proliferation of protein aggregates that are typical for brain diseases such as Alzheimer's disease. These results could provide clues to the question of the extent to which acute or chronic viral infections can influence neurodegenerative diseases.
Aggregates of misfolded proteins, which occur in so-called prion diseases such as Creutzfeldt-Jakob disease, have the ability to pass from one cell to another, where they transfer their abnormal shape to proteins of the same kind. As a result, the disease spreads to the brain. A similar process is discussed for Alzheimer's and Parkinson's diseases, which also involve aggregations of abnormal proteins. The exchange of aggregates can occur by direct cell contact, by release of "naked" aggregates into the extracellular space, or by packaging in vesicles - which are tiny vesicles surrounded by a lipid shell and released for communication between cells. "The exact mechanisms of dissemination are unknown," says Ina Vorberg, research group leader at the DZNE site in Bonn and professor at the University of Bonn. "However, it is an obvious assumption that the transfer of aggregates depends on ligand-receptor interactions both in direct cell contact and via vesicles. This is because in both scenarios, membranes must make contact and fuse. This is easier when ligands are present that bind to receptors on the cell surface and then cause fusion of the two membranes."
Experiments with cell cultures
Based on this assumption, Vorberg's team - supported by colleagues from the DZNE in Munich and Tübingen as well as researchers from Belgium - carried out extensive series of experiments with different cell cultures. They investigated the intercellular transmission of either prions or aggregates of tau proteins, which occur in a similar form in prion diseases or Alzheimer's disease and other "tauopathies". Mimicking what happens as a result of viral infection, the researchers induced the cells to produce viral proteins that mediate binding to target cells and fusion with their membranes. Two proteins were chosen as prime examples: SARS-CoV-2 spike protein S, derived from the COVID-19 pathogen, and the vesicular stomatitis virus glycoprotein VSV-G. The latter is found in a virus that infects cattle and other animals. In addition, cells were used that had receptors for these viral proteins: namely LDL receptors, they are docking sites for VSV-G, and human ACE2, the receptor for the spike protein.
Ligands promote spread of aggregates
"We showed that the viral proteins were incorporated into the cell membrane as well as into extracellular vesicles. Their presence markedly increased the spread of protein aggregates between cells, both by direct cell contact and by extracellular vesicles. The viral ligands ensured efficient transfer or delivery of the aggregates to the recipient cells, in which new aggregates were induced. The ligands act like keys that unlock the recipient cells, allowing the dangerous cargo to enter," said Vorberg. "Certainly, our cellular models do not represent the many aspects of the brain with its very specialized cell types. Nevertheless, we were able to show that regardless of the cell type that produced the pathological aggregates, the viral ligands led to an increased spread of malformed proteins between cells. All in all, our data suggest that viral ligand-receptor interactions can in principle influence the transmission of pathological proteins. This is a novel finding."
Potential impact on neurodegeneration
"In neurodegenerative diseases, certain viruses are sometimes found in the brains of patients. It is suspected that they cause inflammatory reactions or are toxic and thus accelerate neurodegenerative changes. However, viral proteins could also act in another way: they could increase the intercellular spread of protein aggregates, which is already underway in neurodegenerative diseases such as Alzheimer's," Vorberg said. "This now needs to be studied in more detail with viruses that affect the nervous system. The impact of viral infections on neurodegenerative diseases deserves more in-depth study."