Harnessing the brain's repair crew

• A UC Irvine team has engineered microglia – immune cells in the brain – to deliver therapy exactly where it’s needed.
• The approach bypasses the blood-brain barrier, a major obstacle in treating neurological diseases.
• NIH-funded research could lead to personalized treatments for Alzheimer’s and beyond.

Imagine if the brain could heal itself, with its own cells acting as tiny repair crews. That’s the vision driving a team of scientists at UC Irvine who have developed a bold new way to fight Alzheimer’s disease and other neurological disorders.

The challenge has always been the blood-brain barrier, a natural defense system that keeps harmful substances out but also blocks most drugs from getting in. For decades, this barrier has frustrated efforts to deliver therapies where they’re needed most.

Now, UC Irvine researchers have found a workaround: turning microglia – the brain’s resident immune cells – into living, programmable couriers. These engineered cells can sense trouble, like the toxic protein plaques that define Alzheimer’s, and respond by releasing therapeutic enzymes right at the source.

“Delivering biologics to the brain has long been a major challenge because of the blood-brain barrier,” says Mathew Blurton-Jones, professor of neurobiology and behavior and co-lead author of the study. “We’ve developed a programmable, living delivery system that gets around that problem by residing in the brain itself and responding only when and where it’s needed.”

Opening a door to a new class of personalized therapies

The team used CRISPR gene-editing to give microglia a new job: producing neprilysin, an enzyme that breaks down beta-amyloid, the sticky protein that clogs neurons in Alzheimer’s disease. In mouse models, these modified cells didn’t just reduce amyloid buildup – they also calmed inflammation, protected neurons and even improved markers of brain health.

“This work opens the door to a completely new class of brain therapies,” says Robert Spitale, professor of pharmaceutical sciences and co-corresponding author. “Instead of using synthetic drugs or viral vectors, we’re enlisting the brain’s immune cells as precision delivery vehicles.”

The implications are enormous. Beyond Alzheimer’s, the same approach could be adapted for brain cancer, multiple sclerosis, and other neurological conditions. And because the microglia can be derived from a patient’s own cells, future treatments might be personalized – reducing the risk of immune rejection.

The research, published in Cell Stem Cell, was supported by the National Institutes of Health, along with the California Institute for Regenerative Medicine and Cure Alzheimer’s Fund. While human trials are still on the horizon, the concept marks a turning point: a future where the brain’s own defenses become its greatest ally.

What are microglia?

Microglia are the brain’s built-in guardians – tiny immune cells that act like a combination of security guards and janitors. They constantly patrol the brain and spinal cord, looking for anything that doesn’t belong: damaged cells, infections or toxic protein buildup. When they find trouble, they spring into action, cleaning up debris and helping repair damage.

Think of them as the brain’s repair crew, working behind the scenes to keep everything running smoothly. They also help regulate inflammation and support healthy communication between neurons, which is essential for memory and learning.

But in diseases like Alzheimer’s, microglia face an uphill battle. They rush to areas where harmful proteins, such as beta-amyloid, form sticky plaques around neurons. At first, they try to contain the damage. Over time, though, their efforts can backfire – triggering chronic inflammation that makes the disease worse.

That’s why scientists are so interested in microglia. They’re already in the right place, and they naturally respond to signs of trouble. If researchers can reprogram these cells to fight disease more effectively, microglia could become powerful allies in treating Alzheimer’s and other brain disorders.

Updated from the original press release.