Scientists have, for the first time, characterized the molecular markers that make the brain’s front lines of immune defense—cells called microglia—unique. In the process, they discovered further evidence that microglia may play roles in a variety of neurodegenerative and psychiatric illnesses, including Alzheimer’s, Parkinson’s and Huntington’s diseases as well as schizophrenia, autism and depression.
Genes that have previously been linked to neurological diseases are turned on at higher levels in microglia compared to other brain cells, the team reported in a study published in Science.
While the link between microglia and a number of disorders has been explored in the past, the new study offers a molecular basis for this connection.
Microglia are notoriously hard to study. They can't be easily grown in a culture dish and quickly die outside of a living brain. Setting out to characterize the molecular characteristics of microglia, the researchers collected brain tissue from 19 patients, all of who were having brain surgery for epilepsy, a brain tumor or a stroke. They isolated microglia from areas of tissue that were unaffected by disease, as well as from mouse brains, and then set out to study the cells.
The team used a variety of molecular and biochemical tests to characterize which genes are turned on and off in microglia, how the DNA is marked up by regulatory molecules, and how these patterns change when the cells are cultured. Microglia, they found, have hundreds of genes that are more highly expressed than other types of macrophages, as well as distinct patterns of gene expression compared to other types of brain cells.
Next, the researchers analyzed whether any of the genes that were upregulated in microglia compared to other cells had been previously implicated in disease. Genes linked to a variety of neurodegenerative and psychiatric diseases, they found, were highly expressed in microglia.
For Alzheimer's, more than half of the genes known to affect a person's risk of developing the disease were expressed more highly in microglia than other brain cells.
Paper: “An environment-dependent transcriptional network specifies human microglia identity”
Reprinted from materials provided by the Salk Institute.