Brain's immune cells linked to Alzheimer's, Parkinson's, schizophrenia

May 31, 2017
Salk and UC San Diego scientists conducted a vast survey of microglia (pictured here), revealing links to neurodegenerative diseases and psychiatric illnesses. Credit: Nicole Coufal

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.

"Microglia are the of the , but how they function in the human brain is not well understood," says Rusty Gage, professor in Salk's Laboratory of Genetics, the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease, and a senior author of the new work. "Our work not only provides links to diseases but offers a jumping off point to better understand the basic biology of these cells."

Genes that have previously been linked to neurological diseases are turned on at higher levels in microglia compared to other , the team reported in 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."

Microglia are a type of macrophage, found throughout the body that can destroy pathogens or other foreign materials. They're known to be highly responsive to their surroundings and respond to changes in the brain by releasing pro-inflammatory or anti-inflammatory signals. They also prune back the connections between neurons when cells are damaged or diseased. But microglia are notoriously hard to study. They can't be easily grown in a culture dish and quickly die outside of a living brain.

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 . 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, set out to characterize the molecular characteristics of microglia. They 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.

"A really high proportion of genes linked to multiple sclerosis, Parkinson's and schizophrenia are much more highly expressed in microglia than the rest of the brain," says Coufal. "That suggests there's some kind of link between microglia and the diseases."

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 weren't as highly expressed in microglia. "That tells us that maybe mice aren't the best model organisms for some of these diseases," Coufal says.

More work is needed to understand exactly how microglia may be altered in people with diseases, but the new molecular profile of microglia offers a way for researchers to begin trying to better culture the cells, or coax stem to develop into for future studies.

Explore further: Team announces robust, high-throughput protocol for deriving microglia from human stem cells

More information: David Gosselin et al. An environment-dependent transcriptional network specifies human microglia identity, Science (2017). DOI: 10.1126/science.aal3222

Related Stories

Team announces robust, high-throughput protocol for deriving microglia from human stem cells

May 18, 2017
Scientists from the New York Stem Cell Foundation (NYSCF) Research Institute have developed a robust, efficient method for deriving microglia, the immune cells of the brain, from human stem cells. Microglia are increasingly ...

'Housekeepers' of the brain renew themselves more quickly than first thought

January 10, 2017
A study, led by the University of Southampton and published in Cell Reports, shows that the turnover of the cells, called Microglia, is 10 times faster, allowing the whole population of Microglia cells to be renewed several ...

Skin stem cells used to generate new brain cells

April 25, 2017
Using human skin cells, University of California, Irvine neurobiologists and their colleagues have created a method to generate one of the principle cell types of the brain called microglia, which play a key role in preserving ...

Rejuvenating the brain's disposal system

December 21, 2016
A characteristic feature of Alzheimer's disease is the presence of so called amyloid plaques in the patient's brain - aggregates of misfolded proteins that clump together and damage nerve cells. Although the body has mechanisms ...

Study explains mechanisms behind glioblastoma influence on the immune system

September 12, 2016
Glioblastomas exert an influence on the microglia, immune cells of the brain, which causes them to stimulate cancer growth rather than attacking it. In a study published in the journal Nature Immunology, an international ...

The brain may show signs of aging earlier than old age

March 18, 2016
A new study published in Physiological Genomics suggests that the brain shows signs of aging earlier than old age. The study found that the microglia cells—the immune cells of the brain—in middle-aged mice already showed ...

Recommended for you

Brain region mediates pleasure of eating

August 22, 2017
Providing the body with food is essential for survival. But even when full, we can still take pleasure in eating. Researchers at the Max Planck Institute of Neurobiology in Martinsried and the Friedrich Miescher Institute ...

Activating brain region creates intense desire to use cocaine

August 22, 2017
Researchers have identified a portion of the brain that intensifies one's desire for certain rewards—in this case, mimicking addiction to cocaine.

Chronic stress induces fatal organ dysfunctions via a new neural circuit

August 22, 2017
Hokkaido University researchers revealed that fatal gut failure in a multiple sclerosis (MS) mouse model under chronic stress is caused by a newly discovered nerve pathway. The findings could provide a new therapeutic strategy ...

Contact in sports may lead to differences in the brains of young, healthy athletes

August 22, 2017
People who play contact sports show changes to their brain structure and function, with sports that have greater risk of body contact showing greater effects on the brain, a new study has found.

Research reveals 'exquisite selectivity' of neuronal wiring in the cerebral cortex

August 21, 2017
The brain's astonishing anatomical complexity has been appreciated for over 100 years, when pioneers first trained microscopes on the profusion of branching structures that connect individual neurons. Even in the tiniest ...

Afternoon slump in reward response

August 21, 2017
Activation of a reward-processing brain region peaks in the morning and evening and dips at 2 p.m., finds a study of healthy young men published in The Journal of Neuroscience. This finding may parallel the drop in alertness ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.