Throughout history, these cells have been overlooked as mere “foot soldiers” of the immune system.
However, more and more scientists believe that microglia may play a direct role in controlling phenomena ranging from addiction to pain.
Some believe they may even play a key role in diseases such as Alzheimer’s, depression, anxiety, long Covid and myalgic encephalomyelitis (ME), also known as chronic fatigue syndrome.
But, What exactly are microglia?
There are two types of cells that make up the brain.
Neurons, also known as nerve cells, are the brain’s messengers, sending information throughout the body through electrical impulses.
The other type, the glia, make up the rest. The Microglia are the smallest member of the glia family and represent approximately 10% of all brain cells.
The small cells have an oval-shaped central “body” from which thin tendril-like arms emerge.
“They have many branches that continually move to survey their environment,” says Paolo d’Errico, a neuroscientist at the University of Freiburg, Germany. “Under normal conditions, they extend and retract these processes to perceive what is happening around them.”
When they work well microglia They are essential for healthy brain function. During our early years, they control brain development by pruning unnecessary synaptic connections between neurons.
They influence which cells become neurons and repair and maintain myelin, a protective layer of insulation that covers neurons, without which the transmission of electrical impulses would be impossible.
Its function does not end there.
Throughout our lives, microglia protect our brain from infections by seeking out and destroying bacteria and viruses.
They clear debris that builds up between nerve cells and remove and destroy misshapen toxic proteins, such as amyloid plaques (the groups of proteins thought to play a role in the progression of Alzheimer’s disease).
Nevertheless, Under certain circumstances they can become uncontrollable.
“Microglia have two faces: a good one and a bad one,” says Linda Watkins, a neuroscientist at the University of Colorado at Boulder.
“They look for problems, unusual neural activity, and damage. They’re on the lookout for any kind of problem inside the brain, but when they get too excited, they go from being the good watchers to the pathologically bad ones.”
What makes them become rebellious? When microglia They detect that something is wrong in the brainlike an infection or a large presence of amyloid plaques, they go into a state superreactive.
“They get much bigger, almost like big balloons, and they retract their appendages and start moving around, gobbling up the damage like little Pac-Mans,” Watkins says.
Activated microglia also release substances known as inflammatory cytokines, which act like a beacon, calling other immune cells and microglia into action.
This response is necessary to help the body fight invaders and threats. Typically, after a certain amount of time, the microglia return to their “good” state.
But sometimes it appears that microglia can remain in this overexcited state long after the infectious agent has disappeared.
Now it is thought that these Out of control microglia are the cause of a variety of diseases y conditions modern.
Take addiction as an example. This condition has historically been considered a disorder of the dopamine neurotransmitter system, and dopamine imbalances are responsible for patients’ increasingly drug-focused behavior.
But Watkins has a different theory.
In a recently published academic paper, Watkins and scientists from the Chinese Academy of Sciences argue that when a person takes a drug, their microglia see the substance as a foreign “invader.”
“What we discovered through our own research was that a variety of opioids activate microglial cells, and they do so at least in part through what’s called the ‘Toll-like receptor’ (TLR),” Watkins says.
“Toll-like receptors are very old receptors designed to recognize foreign objects. They’re supposed to be there to detect fungi, bacteria and viruses. They’re the ‘it’s not me, I’m not okay, I’m not okay’ receptors.”
When microglia detect drugs such as opiates, cocaine or methamphetamine, they release cytokines, which causes the neurons that are active at the time of taking the drug to become more excitable.
Crucially, this leads to the formation of new, stronger connections between neurons and the release of more dopamine, which reinforces the desire and the anxiety for the drug.
Microglia change the very architecture of the brain’s neurons, leading to drug-taking habits that can last a lifetime.
The evidence supporting this theory is compelling.
For one thing, drug addicts see increased inflammation and inflammatory cytokines in the brain. Reducing inflammation in animals also reduces drug-seeking behavior.
Watkin’s team has also shown that mice can be prevented from continuously seeking drugs such as cocaine by blocking the TLR receptor and preventing activation of the cell itself.
Microglia may also play an important role in chronic paindefined as pain lasting more than 12 weeks.
Watkins’ lab has shown that after an injury, microglia in the spinal cord become activated, releasing inflammatory cytokines that sensitize pain neurons.
“If the activation of microglia or their pro-inflammatory products is blocked, pain is blocked”afirma Watkins.
According to Watkins, microglia could explain even another phenomenon: why older people experience a marked decline in their cognitive abilities after surgery or infection.
Surgery or infection acts as a first blow that “primes” the microglia, making them more likely to adopt their bad condition.
After surgery, patients are often given opioids to relieve pain, which unfortunately activates microglia again, causing a storm of inflammation that ultimately leads to the destruction of neurons.
The research field is in its infancy, so These early findings should be taken with caution.but studies have shown that postoperative memory decline in mice can be prevented by blocking their microglia.
“If I walk up to you and, without warning, I slap you, I get away with it the first time. But you don’t let me get away with it the second time because you’re prepared, you’re ready, you’re on guard,” says Watkins. .
“Glial cells are the same. With aging, glial cells become increasingly primed and ready to overreact as the years go by. And now that they are in this optimal state, a second challenge is how surgery makes them come into action with much more force than before. “Then there are opioids, which are a third strike.”
Chronically activated microglia can engulf and kill neurons directly, release toxic reactive species that damage them, or initiate “over-pruning” of synapses, destroying the connection between nerve cells.
All of these processes could ultimately lead to the confusion, memory loss, and loss of cognitive function that characterize the disease.
In a 2021 study, d’Errico even found that microglia may contribute to the spread of Alzheimer’s disease by transporting toxic amyloid plaques through the brain.
“In the early stages of Alzheimer’s there are particular regions in the brain that appear to accumulate plaques, such as the cortex, hippocampus, and olfactory bulb,” says d’Errico.
“In the later stages of the disease there are many more regions affected. We found that microglia are able to internalize the amyloid protein and then move to another region before releasing it again.”
Some of the symptoms of Alzheimer’s, such as poor memory and loss of cognitive function, are similar to those suffered by long Covid, and it’s possible that wandering microglia could also be behind ‘brain fog’.
For example, one of the main factors that causes microglia to go rogue is the presence of a viral infection.
“Abnormally activated microglia can initiate excessive pruning of synapses in the brain, and this can lead to cognitive impairment, memory loss and all those symptoms related to brain fog syndrome,” says Claudio Alberto Serfaty, a neurobiologist at the Fluminense Federal University, in Rio de Janeiro, Brazil, who summarized the evidence for this theory in a recent article.
The hope is that this new way of thinking will eventually lead to new treatments.
Clinical trials of new Alzheimer’s drugs are currently underway that aim to increase the ability of microglia to destroy amyloid.
However, as with all medications for this condition, the strategy would work best in the early stages of the disease, before significant neuronal death has occurred.
In the case of addiction, an idea is replace erratic microglia that have stopped functioning correctly with “normal” microglia present in the brains of those who do not use drugs.
This concept, known as microglia replacement, involves grafting the cell into specific regions of the brain through a bone marrow transplant.
However, this approach would be difficult. After all, active microglia are necessary to fight infections; in fact, it is vital for brain function.
“In theory, it could work, but you have to keep in mind that you don’t want to alter microglia throughout the brain, but rather they would have to be localized,” says Watkins.
“Microinjecting microglia into specific areas of the brain would be very invasive. That’s why I think we have to look for something that is safe for that type of treatment,” he adds.