Swapping out the brain’s cleanup crew treats neurological disease in mice, study shows

From anemia to leukemia, unhealthy cells can make for unhealthy people, but replacing these cells can help patients. What if the same were true for some of the world’s most devastating neurological diseases?

A new study published Wednesday in Science Translational Medicine raises the tantalizing possibility that researchers could one day replace microglia — cells that form a roaming cleanup crew that scours the brain for signs of infection and damage. A team led by Stanford scientists found microglia could be swapped out in mice with an infusion of stem cells as part of a bone marrow transplant. Doing so helped mice with a neurodegenerative disease live longer and move about more normally.

The study’s authors and observers say it’s the first-ever study to report that microglia replacement can help treat a disease. But there’s no guarantee the finding holds up in people. And researchers say they’d first want to tweak the procedure so that it’s less toxic.

Still, the findings raise hopes that isolating a person’s blood stem cells, correcting their genetic errors, and reintroducing those cells could remedy microglia defects in a wide range of brain diseases, from rare neurological conditions to Alzheimer’s.

“Essentially, any genetic disease that affects microglia would be a fantastic target,” said Marius Wernig, a stem cell researcher at Stanford and senior author of the study. “Because in this case, you know that you fixed the problem.”

Scientists’ understanding of what microglia do — and why that matters — has changed dramatically over the years. These spindly looking cells were once overshadowed by neurons, but researchers now know that they are the brain’s resident immune cells, a sort of local police force that gobbles up dead, derelict cells.

Microglia also profoundly shape one of the brain’s most fundamental processes: making memories, which are hard-wired as connections between neurons. These cells can literally eat up these connections, influencing what we remember and how we learn.

Several DNA mutations linked to neurological disease are in genes associated with microglia. And biotech companies have taken notice. Vigil Neurosciences of Cambridge, Mass., is working on a microglia-focused treatment for a rare neurodegenerative disorder called adult-onset leukoencephalopathy. And Bay Area biotech Alector is developing three different Alzheimer’s drugs that target microglia.

In the present study, Wernig’s team tested what it hopes could be a more direct and longer-lasting solution: replacing defective microglia altogether. Doing so wasn’t straightforward. That’s because while the standard way to replace immune cells is through a bone marrow transplant, the procedure doesn’t efficiently replace microglia, which normally don’t rely on bone marrow cells to maintain their own numbers within the brain.

So the authors tried a different tack. Shortly after the transplant, they injected mice with a chemical that blocks a key pathway for microglia growth and survival. Doing so cleared out existing microglia, and these cells were quickly replenished with transplanted cells. Under the microscope, the cellular carpetbaggers, tagged with a protein that made them glow green, looked like a twinkling constellation across the brain.

“When I first saw these pictures, I was blown away,” said Wernig, who has spent 20-plus years struggling to get cells to migrate through the brain. “That is exactly what we had tried for so many years to accomplish. And now, all of a sudden, we had a recipe.”

Other researchers have successfully used a similar recipe, including a French group that published their findings in Nature Medicine in February. Wernig suspects the combination of pre-transplant chemotherapy and microglia clearing allows the transplanted cells to cross into the brain and ensures they’ll have space to make a new home when they arrive.

The authors tinkered with infusing different cell types to see which was best for replacing microglia. They found that hematopoietic stem cells — which can become virtually any type of blood cell — made for the best transplant material.

They also found that while the new arrivals to the brain looked and acted like microglia, they weren’t quite identical to the cells they replaced. In some cases, they were more apt to munch on cellular debris than standard microglia. And there were subtle differences in how the transplanted cells and native microglia activated various genes.

The team then tried to do something no one had done before: show that swapping out microglia could help treat disease. To do so, scientists worked with a strain of mice that develops a neurodegenerative disease triggered by low levels of a protein called prosaposin in multiple cell types — including microglia. Replacing microglia in these mice with cells from mice that didn’t have a key mutation caused the animals to have more normal balance and movement. The mice also survived longer.

“Definitely interesting, and maybe, potentially translationally relevant,” said Susan Kaech, an immunologist at the Salk Institute who studies microglia and was not involved in the study.

She added that she was surprised the authors didn’t use an Alzheimer’s mouse model since there are mouse strains that carry disease-associated genes in microglia. The model the authors used isn’t a perfect mimic of any one human neurodegenerative disease, but it’s used to study some aspects of Gaucher disease, a rare metabolic disorder that can trigger neurological symptoms.

Wernig’s team now plans to test whether their findings hold up in monkeys. They’re also grappling with how to make the transplant protocol less toxic. Treating a patient with chemotherapy or radiation before a bone marrow transplant is routine. But in this case, researchers are trying to replace cells in the brain, not the bone marrow, so they’re hopeful they can find another solution that would induce fewer side effects. It’s also unclear whether the differences the scientific team has seen between the replacement cells and native microglia are important, Wernig adds, and, if so, whether that’s helpful or harmful.

“Bottom line, it has to be tested,” he said.