Salk and UC San Diego scientists conducted vast microglia survey, revealing links to neurodegenerative diseases and psychiatric illnesses.
Scientists have, for the first time, characterized the molecular markers that make the brain’s front lines of immune defense 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 the journal Science on May 25, 2017. 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.

“These studies represent the first systematic effort to molecularly decode microglia,” says Christopher Glass, a Professor of Cellular and Molecular Medicine and Professor of Medicine at University of California San Diego, also senior author of the paper. “Our findings provide the foundations for understanding the underlying mechanisms that determine beneficial or pathological functions of these cells.”

Nicole Coufal, a pediatric critical care doctor at UC San Diego, who also works in the Gage lab at Salk, wanted to make microglia from stem cells. But she realized there wasn’t any way to identify whether the resulting cells were truly microglia.

“There was not a unique marker that differentiated microglia from circulating macrophages in the rest of the body,” she says.

David Gosselin and Dylan Skola in the Glass lab, together with Coufal and their collaborators worked with neurosurgeons at UC San Diego to collect 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 work was made possible by a multidisciplinary collaboration between bench scientists, bioinformaticians and clinicians.

The team used a variety of molecular and biochemical tests – performed within hours of the cells being collected – 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. After the cells were cultured, however, the gene patterns of the microglia began to change. Within just six hours, more than 2,000 genes had their expression turned down by at least fourfold. The results underscore how dependent microglia are on their surroundings in the brain, and why researchers have struggled to culture them.

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.

In mice, however, many of the disease genes weren’t as highly expressed in microglia.