Microglia: a new target in the brain for depression, Alzheimer’s, and more?

More than a decade ago, I was diagnosed with a string of autoimmune diseases, one after another, including a bone marrow disorder, thyroiditis, and then Guillain-Barré syndrome, which left me paralyzed while raising two young children.

I recovered from Guillain-Barré only to relapse, becoming paralyzed again. My immune system was repeatedly and mistakenly attacking my body, causing the nerves in my arms, legs, and those I needed to swallow to stop communicating with my brain, leaving me confined to — and raising my children from — bed.

As I slowly began to recover and learn to walk again, I noticed that along with residual physical losses I had experienced shifts in my mood and clarity of mind. Although I’d always been an optimistic person, I felt a bleak unshakable dread, which didn’t feel like the “old me.”

I also noticed cognitive glitches. Names, words, and facts were hard to bring to mind. I can still recall cutting up slices of watermelon, putting them in a bowl, and staring down at them thinking, “What is this again?” I knew the word but couldn’t remember it. I covered my lapse by bringing the bowl to the table and waiting for my children to call out, “Yay! Watermelon!” And I thought, “Yes. Of course. Watermelon.”

As a science journalist whose niche spans neuroscience, immunology, and human emotion, I knew at the time that it didn’t make scientific sense that inflammation in the body could be connected to — much less cause — illness in the brain. At that time, scientific dogma held that the brain was the only organ in the body not ruled by the immune system. The brain was considered to be “immune privileged.”

That began to change in the early 2010s. As neuroscience and immunology started to merge, they began dismantling that century-old tenet. Scientists pivoted away from believing that the brain and body function as church and state entities, and developed an entirely new brain-body paradigm which acknowledges that the brain is also governed by the immune system.

Much of the revelatory science fueling this reversal in how we see brain health was due to a radically new understanding of tiny cells called microglia. In healthy brains, microglia act as humble housekeepers, removing dead cells and bathing neurons in protective factors. A new understanding of these cells tells us that when they go rogue, they destroy synapses and cause inflammation in the brain.

In 2012, Beth Stevens, a young researcher at Children’s Hospital and Harvard Medical School, and her then-postdoc, Dori Schafer, discovered that microglia also determine synaptic health, for good or ill, from cradle to grave — a discovery for which Stevens was named a 2015 MacArthur “genius award” winner. They showed that these cells, which scientists had ignored since they were first noted in the 1920s, were actually powerful immune cells.

But just as the body’s immune system can rev into overdrive, causing inflammation and devastating physical symptoms, microglia can also become overexcited. When that happens, they can generate too much synaptic pruning, neuroinflammation, and symptoms of cognitive, mood, and behavioral disorders, from depression to Alzheimer’s disease.

This revelation, while scary to contemplate if you are a patient like me, is also the springboard for promise with a newly emerging and innovative set of tools that may help intervene in mental health disorders by treating the brain’s immune pathways much as we treat immune disorders of the body.

It turns out that people who have high levels of chronic inflammation, as measured by simple blood tests, also have higher levels of microglial activation in the brain, a keen and worrisome indicator that too many synapses are being lost.

This month, four hospitals from the National Network of Depression Centers — the Mayo Clinic, University of Michigan, Johns Hopkins Hospital, and Emory University — are wrapping up a clinical trial known as the Bio-K Study. It is investigating whether measuring individuals’ levels of inflammation and other related biomarkers can predict if infusions of ketamine (the “K” in the study name) will ease their depression. Originally used as an anesthetic, ketamine has been shown to have powerful antidepressant effects, and appears to work as an anti-inflammatory in the brain.

The Bio-K study is fueled by recent discoveries that individual differences in patients’ physical health can affect how well a treatment for depression helps the brain repair itself. Of particular interest is how inflammation, which can signal microglia to become overactive and destroy synapses in areas of the brain related to symptoms of depression and bipolar disorder, might limit someone’s response to treatment.

The Bio-K investigators are measuring participants’ levels of chronic inflammation before they receive ketamine infusions. After the infusions, blood samples are checked again to determine if changes in biomarkers are associated with improved outcomes.

If the findings are positive, it will help clinicians determine if inflammation is associated with patients’ positive, neutral, or negative responses to treatment, and may help them predict which treatments are best for which patients.

At Emory University School of Medicine, researchers have found that inflammation is linked to weakened reward circuits in depression — and they can predict which patients’ neural circuits are going dark by measuring their level of inflammation via a simple blood draw. Also underway at Emory are clinical trials looking at the viability of using the same anti-inflammatories employed to treat autoimmune disease, such as infliximab, to treat depression. The hope is that by getting overexcited microglia to back off, important regions of the brain will be able to communicate again.

This new understanding of the working of the immune system in the brain is also leading to a clearer understanding of which oral antidepressant will work best in which patient. It turns out that for individuals who test positive for chronic inflammation, bupropion (Wellbutrin) may work better than drugs like escitalopram (Lexapro).

Immunotherapy also appears to show promise in treating Alzheimer’s disease. Last spring, news broke that Enbrel, Pfizer’s powerhouse anti-inflammatory drug for rheumatoid arthritis, appeared to help prevent Alzheimer’s disease. In data collected by a computer analysis of over 250,000 insurance claims, the drug reduced the risk of Alzheimer’s disease by 64% in patients who took it.

Others have picked up this research thread, and a number of labs are targeting the ways microglia express genes that increase the risk of Alzheimer’s. Piggybacking on work by an international team of researchers who identified a genetic mutation that seems to protect people from developing Alzheimer’s disease, Alector, an early-stage biotech company, identified a drug candidate called AL014 that shifts microglial gene expression in ways that prompt microglia to turn from the dark side to the light and begin clearing the brain of unwanted toxins. In theory, that may help stave off the onset of Alzheimer’s.

Why mental health disorders can be so difficult to treat in some people and not others is a mystery. The idea that microglia-led inflammation — triggered by a combination of genes and environmental factors from emotional trauma to toxins — can slowly brew within the brain throughout an individual’s lifetime offers a clue to that enigma.

When microglia go haywire, they destroy synapses and neural connections in the brain that affect mood and behavior. There can be many consequences: overreaction to small problems, a dearth of joy, entrenched depression, pernicious anxiety, forgetfulness, lost memories. No two individuals’ brains are the same.

Over time, many small changes in neurocircuitry wrought by inflammation-led microglia can cause individuals to feel and behave very differently from the persons they once were or the ones they hoped to become.

Although the excessive forgetfulness I experienced in my post-paralysis years no longer plagues me, it’s been replaced by the kind of age-related glitches we all face. Having once struggled to add simple numbers and recall familiar words, I’m eager to avoid going through that again. So I’m keeping an eye out for where these trials lead, bearing in mind the first rule of medicine: We must first be sure to do no harm, and proceed with an abundance of caution.

As I get older, will I be brave enough to try an anti-inflammatory to help calm down the microglia that govern the 3-pound jelly universe that is my brain? I have a little time to decide. But not too much.

Donna Jackson Nakazawa is a science journalist and author of six books, including “The Angel and The Assassin: The Tiny Brain Cell That Changed the Course of Medicine” (Random House/Ballantine, January 2020).