Experts have long thought of microglia as the immune cells of the brain because they support and defend cells within the central nervous system. To help describe their various functions, scientists have classified microglia into three different roles: sentinels, warriors and nurturers. But what happens to the brain when these microglia aren’t doing their job properly?

In a recent review article published in Nature Neuroscience, a team of researchers at Mass General, including Suzanne Hickman, PhD, and Joseph El Khoury, MD, for the first time, were able to provide a more precise description of how dysfunctional microglia can contribute to neurodegenerative diseases like Alzheimer’s and Parkinson’s.

They suggest that if microglial activity can be regulated, they may be able to reduce inflammation and damage done by these diseases.

The Three Roles of Microglia

Microglia are vital to the central nervous system. When functioning properly, they are constantly migrating through the brain as sentinels, warriors and nurturers.

Sentinel microglia are crucial because they act as the brain’s security. They are constantly in motion monitoring their surroundings and sensing changes to make sure everything is in order. If sentinel microglia detect any harmful proteins or other stimuli, the warrior microglia come to the rescue.

Warrior microglia bring the muscle. They are stockier in body and fight against infectious pathogens and harmful proteins. Once they come into contact with harmful stimuli, they can express receptors and initiate a neuroinflammatory response to help neutralize the threat.

Nurturing microglia play a significant role in maintaining homeostasis and overall well-being within the brain. They perform housekeeping functions by removing dying cells and unnecessary debris.

Microglia and Neurodegenerative Diseases

A Mass General research team evaluated patterns of gene expression within microglia to get to the bottom of their three specific functions. By investigating the patterns, they were able to figure out how certain neural processes could go wrong and create problems often seen in diseases like Alzheimer’s, Parkinsons, multiple sclerosis, Huntington’s and others.

One of the main signs of Alzheimer’s disease is the accumulation of a protein called beta-amyloid. In a healthy brain, nurturing microglia would help regulate the amount of beta-amyloid. Research shows that when microglia cannot keep up with the amount of beta-amyloid being produced, an inflammatory response is triggered, which leads to further damage and inflammation.

Scientists found that a similar situation is seen in the development of Parkinson’s disease. Nurturing microglia, which initially serve as protection, end up being transformed into an unregulated, disease-associated form that leads to continuous inflammation and damage.

How Regulating Microglia Can Help

Using these findings, researchers have been able to gather that neurodegenerative issues usually arise when out-of-control microglia act outside of their roles and cause excessive neuroinflammation. They believe that by activating three potential immune checkpoints, they may be able to convert damaging microglia back to their protective state.

“Expanding studies from animal models to human patients remains a challenge that will require development of new, reliable cellular models based on patient samples and additional technologies for imaging and analysis. And new techniques to incorporate microglia into three-dimensional organoids – miniature organs grown from living tissues – are a crucial next breakthrough that needs to be achieved.”

Joseph El-Khoury, Principal Investigator, Center for Immunology and Inflammatory Diseases

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