Mighty Microglia – The Brain’s Immune Cells Key to Treating Brain Diseases

Microglia, the immune cells of the brain, were long thought to be rather boring cells that existed in only two states — resting and activated. It was long believed that in the healthy brain microglia lay waiting doing nothing until serious damage was detected. If the brain was infected or damaged, microglia were thought to respond similarly to the immune cells in the rest of the body — swelling, fighting invading micro-organisms, then returning to a resting state and doing nothing further. However, over the past few years, increasingly sophisticated experiments have demonstrated that these cells are capable of a wide range of unexpected activities and responses. As a result, these previously ignored cells are turning out to be promising targets for new drugs to treat a wide range of neurodegenerative disorders.

Microglia, it turns out, actually play an important role in keeping the brain healthy. Improved microscopy has been able to show that while these cells appear to be “resting”, they, in fact, have very fine processes extending out from the cell bodies constantly searching the brain for damage. It has been estimated that every few hours the entire human brain has been checked for health. Like a sentry in a watchtower, in order to stay in this surveillance state microglia require a constant, “all is well,” signal from the surrounding cells. If they fail to receive this signal, the microglia jump into action to investigate the problem.

If damage has occurred, microglia are also capable of a sophisticated range of responses depending on the level of damage. If the damage is small, cells can send out a “find me” signal. The microglia are activated to a protective state and seek out these cells. They attempt to stabilise the damage and protect the nearby neurons. However, if the damage is greater or more dangerous to surrounding tissue, these cells will send out an “eat me” signal. The microglia then become fully activated to a toxic state. They can kill infected cells before infection spreads and clear any debris from damaged or dying cells.

Microglia thus must effectively decide whether to protect or destroy cells in response to insults. Unfortunately, as the brain ages, these cells seem to become less efficient at reacting. The same signal that induces microglia to a protective state in a young brain may induce a fully activated, toxic state in an older brain. It appears that in older brains, microglia overreact to damage and disease. Instead of protecting brain tissue from further damage, they aggravate the problem by becoming fully activated and attacking healthy brain cells.

Microglia are, therefore, a very interesting target for therapies for all neurodegenerative diseases such as Parkinson’s Disease, Alzheimers Disease, multiple sclerosis, stroke, and so on. The goal of many scientists is now to differentiate the types of signals that control the states of activation of microglia and exploit these in creating new drugs. While calming the microglia into a protective state will not cure the underlying neurodegenerative disorders, it could slow the damage and disease progression. This may even help the brain repair some of the damage, recover lost tissue, and ease the symptoms of these diseases.

References

Kettenmann, H., Hanisch, U., Noda, M., & Verkhratsky, A. (2011). Physiology of Microglia Physiological Reviews, 91 (2), 461-553 DOI: 10.1152/physrev.00011.2010

Nimmerjahn, A. (2005). Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo Science, 308 (5726), 1314-1318 DOI: 10.1126/science.1110647

Hanisch, U., & Kettenmann, H. (2007). Microglia: active sensor and versatile effector cells in the normal and pathologic brain Nature Neuroscience, 10 (11), 1387-1394 DOI: 10.1038/nn1997

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