Refreshing the Brain’s Immune Cells Could Treat a Host of Diseases

Microglia are the silent guardians of the brain. They hunt down pathogens, clean up toxic protein clumps, and even shape the brain’s wiring. They’re also robust. Neurons can’t divide to generate new copies of themselves. But microglia can renew, especially during inflammation, stroke, or diseases that erode cognition.

And yet this regenerative ability has a limit, especially when the cells harbor genetic mutations. One solution? Replace diseased or injured cells with a fresh supply.

This year saw a meteoric rise in microglia replacement therapy, with clinical trials highlighting its brain-protecting potential. Refreshing microglia could, in theory, boost their beneficial effects.

Tinkering with the brain’s complex immune system isn’t straightforward, but “microglia replacement has emerged as a groundbreaking paradigm,” wrote Bo Peng and colleagues at Fudan University. The therapy could tackle a range of conditions from rare genetic diseases to more familiar foes such as Alzheimer’s.

Tough Nut

Microglia are odd ducks. Like other immune cells that patrol the body, they usually start out as blood stem cells in bone marrow before migrating to the brain. Once settled, they stay at their post, exclusively protecting the brain.

The cells are usually shaped like shrubs in need of a haircut. But once activated, they shrink into puff balls and recruit other brain cells to fight off invaders and prevent brain damage.

Microglia also reconfigure the brain’s wiring. They prune extra synapses—connection points that allow neurons to talk to each other—and pump out nutritious molecules to support established neural networks and encourage baby neurons to grow.

It’s no wonder that when microglia go awry so does the brain. This happens in Alzheimer’s, other neurodegenerative diseases, and even just as we age. But more commonly, it’s because of genetic mutations in the cells.

Gene therapy is seemingly the best way to fix these problems. But microglia are notoriously terrible candidates. A gene therapy is usually shuttled into cells within safe viral carriers or tiny bubbles of fat. Few of these can enter the brain’s immune cells. Microglia-specific carriers exist, but they need to be injected directly into the brain. Complications from surgery aside, injected cells only reach a small area—hardly enough to make a notable difference.

Microglia replacement gets around this roadblock. Replacing mutated or aged cells with a healthy supply could correct genetic problems and “replenish populations lost to degeneration, inflammation, or developmental failure,” wrote Peng and colleagues.

A Harrowing Swap

Transplanting healthy donor microglia directly into the brain is nearly impossible because existing microglia often turn against the new arrivals. But because microglia start life as blood stem cells, a bone marrow transplant from a healthy, matching donor is a viable alternative. Once mature, the cells journey to the brain, where they divide and thrive.

The first and most taxing step of a bone marrow transplant is making space for the new cells. This requires extensive radiation or chemotherapy, but often without direct treatment to the head. The step also destroys the recipient’s immune system, leaving them vulnerable to infections and at higher risk for cancer.