Microglia: The protectors of the brain

by Muhammet M. Ozturk
figures by Wei Wu

For decades, scientists have been intrigued by how the brain controls the body. This curiosity led them to discover neurons, the brain’s messenger cells. Neurons, which receive, transmit, and process information, are arguably the most famous cells in our brain. The attention they get might suggest that the brain is only made up of neurons. However, about half of the mass of our brain is made up of non-neuronal cells called glia (a Greek word meaning glue). Glia are generally smaller but more numerous than neurons and support the functions of the neurons in the brain. But how exactly do glial cells support neurons?

When we take a closer look at the brain, we see three types of glial cells (Figure 1): first, the star-shaped cells, astrocytes, support communication between neurons. Second, oligodendrocytes speed up the transmission of information, allowing neurons to communicate quickly. Lastly, the smallest type of glial cell is known as microglia, which has begun to draw more attention in recent years. Although microglia only make up about 10% of all brain cells, these inconspicuous members of our brain work to create a stable environment by keeping our brain clean and healthy, thus allowing neurons to perform their vitally important functions. Because microglia are so critical for the maintenance of neuronal function, scientists naturally asked the question: how do microglia perform such an important job, and what happens if they go rogue?

**Figure 1.** In the brain, there are 3 main glial cell types that support neurons to keep our brain healthy: a) **astrocytes** help communication between neurons, b) **oligodendrocytes** create conditions for the information to be transmitted faster, and c) **microglia** act as the immune system of the brain.

What role do microglia play in maintaining brain health?

So, what exactly does it mean for microglia to keep our brains clean and healthy? Our brain is generally highly protected against invaders, thanks to the bodyguard of the brain, the Blood-Brain Barrier (BBB). The BBB is a selective wall of cells that acts as the brain’s first line of defense, preventing unwanted substances and pathogens that circulate in our blood from entering the brain (Figure 2).

**Figure 2.** The Blood-Brain Barrier (BBB) is a selective wall of cells and surrounding blood vessels that protects the brain from foreign invaders by preventing their entry. Some small invaders can pass through, but the immune cells that fight them in the rest of the body cannot. Instead, microglia act as the immune cells of the brain. Inactive microglia (in yellow) survey the environment. When they detect invaders, they become activated (in orange) and change their shape by flattening and shortening their arms so that they can clean up the invaders.

While this specialized barrier can keep bad substances out of the brain, it can sometimes be too strict a barrier for the brain’s own good: immune cells, which fight illness in the rest of our body, are also unable to cross the BBB under normal conditions. So, how does the brain protect itself if something harmful makes it through the BBB? In addition to fighting off infections, immune cells also perform many crucial cleanup tasks in the rest of the body. Without immune cells, how does our brain get rid of cellular waste and dead cells? The brain’s answer to these problems is microglia, the resident immune cells of the brain.

Even in a healthy brain, microglia perform many essential maintenance functions. For example, microglia remove neurons that don’t communicate properly, thus ensuring that information transfer between neurons is not interrupted. Microglia also help clean up protein aggregates, clumps of abnormally shaped proteins that accumulate and are associated with neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s disease.

The most famous function of microglia is their role as the immune system of the brain. Like immune cells do in the rest of the body, microglia continually inspect the brain environment for signs of trouble. What makes microglia unique compared to other immune cells is how they inspect the environment: microglia have long and highly dynamic arms, allowing them to extend and retract in all directions, checking the environment to make sure that there is no danger. If they don’t detect invaders, they stay in their resting (inactive) state. However, when they sense a threat, they become active and initiate the process of inflammation, which is the body’s reaction against the infection. Their shape dramatically changes, with their arms shortening and their bodies flattening (Figure 2). Then, the activated microglia multiply, move to the infected site, and get rid of whatever is dangerous by engulfing it, just like a cleanup crew (Figure 3).

What if microglia lose control?

Although microglia protect the brain from diseases, they might also cause disease under the wrong conditions. Normally, once an external threat (such as a virus) is detected by microglia, microglia cause targeted inflammation as an important protective mechanism to kill the invader. However, if the inflammation lasts for a prolonged time, the process can start to destroy healthy brain cells. Uncontrolled inflammation caused by microglia in the brain has been implicated in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, or Amyotrophic Lateral Sclerosis.

Microglia in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Motor neurons, which control our muscle movements, die in ALS, paralyzing patients with the disease. But what causes this motor neuron death? Some scientific research points to microglia as one of the prime suspects. Initially, microglia help fight off ALS by clearing the threats to functional motor neurons. However, since prolonged microglial activity can cause healthy motor neurons to die, microglial activities may also cause the disease to progress more rapidly. Since overactive microglia can impact motor neurons in ALS, microglia have become a target in developing therapies for the disease.

**Figure 3.** In the early stages of ALS, microglia may have a protective role by detecting and clearing away dead motor neurons (top). However, in the presence of chronic inflammation (bottom), overactive microglia can contribute to the death of healthy neurons, which may cause the disease to progress more rapidly.

While much has been discovered about the role of microglia, there are still many unanswered questions about their role in disease that require further investigation. For example, scientists have been working to find a way to specifically eliminate diseased microglia without causing any harm to other healthy brain cells so as to decrease the severity of neurodegeneration. No matter what future research on microglia shows, however, one thing is certain: these protectors of the brain will remain an interesting and integral part of our brain’s ecosystem!

Muhammet M. Ozturk is a postgraduate associate at Harvard Medical School and is currently working on certain ALS-causative RNA/DNA binding proteins regulating immune genes.

Wei Wu is a graduate student in the Design Studies program at Harvard University Graduate School of Design. Her concentration is Art, Design, and the Public Domain.

Cover image by geralt from pixabay

For more information:

Check out this article describing the brain’s messenger cells, neurons, in detail.
If you would like to see what these spectacular glia cells look like, visit here.
Want to learn more about what else the immune system does? Read here about some of its unexpected functions.
Microglia are not alone in killing motor neurons. Read this greatly detailed study to learn who is helping microglia to damage motor neurons.
Read more information about microglia might be a good target for treating neurodegenerative diseases such as Alzheimer’s disease.
Did you know some immune cells enter the brain in ALS? Check out this study to learn more.