Meet microglia: The brain’s secret weapon against Alzheimer’s

In the search for answers about Alzheimer’s disease, researchers are taking a close look at the immune system of the brain. A new study uncovers how a key immune cell, called a microglia, might be the brain’s secret weapon against the buildup of toxic proteins that lead to memory loss and confusion. Scientists have identified a special receptor that helps these immune cells keep the brain clean and healthy—and losing it could mean trouble.

Alzheimer’s disease causes the brain to slowly deteriorate. One of its most damaging effects is the buildup of a sticky protein called amyloid beta. These proteins cluster together into harmful clumps known as plaques. Over time, they damage nerve cells, making it hard to think, remember, and learn. But not everyone with these plaques experiences the disease in the same way. Some people show milder symptoms, and researchers wanted to know why.

Microglia are immune cells that act like the brain’s janitors. They search for and clean up unwanted materials, including amyloid beta. These tiny cells are born from yolk-sac-derived tissue early in development and remain in the brain for life. They don’t just remove trash—they also help maintain balance, fight infections, and repair damage.

In some people, microglia work better than in others. Scientists at UC San Francisco studied this difference using a mouse model of Alzheimer’s disease called 5xFAD. These mice carry five mutations linked to Alzheimer’s and develop symptoms similar to those in humans, including amyloid plaque buildup and memory problems. What they found could change how researchers treat the disease.

At the center of the discovery is a receptor called ADGRG1. This protein sits on the surface of microglia and plays a critical role in how they function. It belongs to a large family of proteins known as adhesion G protein-coupled receptors (aGPCRs), which are often involved in cell communication and are common targets for drug development.

When the scientists deleted the gene for ADGRG1 in microglia, the results were dramatic. Without it, the microglia could barely touch the amyloid beta. The plaques grew quickly, and the mice showed worse brain damage and severe memory issues. Their brains lost more neurons, and they struggled with tasks that normal mice could perform easily.

The presence of ADGRG1 had the opposite effect. When active, it set off a chain reaction inside the microglia, activating a key transcription factor called MYC. MYC turned on several genes responsible for essential tasks like clearing waste, digesting harmful substances, and keeping the microglia in a healthy state. In short, ADGRG1 gave microglia the power to fight Alzheimer’s at the cellular level.

To understand how this might apply to people, the team reanalyzed brain samples from past Alzheimer’s studies. In individuals who died with only mild symptoms, microglia had high levels of ADGRG1. This suggested they were actively clearing amyloid beta and slowing the disease. But those with severe Alzheimer’s had low levels of ADGRG1. Their microglia had stopped doing their job, allowing plaques to spread and symptoms to worsen.

“This receptor helps microglia keep the brain healthy over many years,” said Xianhua Piao, MD, PhD, a pediatric neurologist at UCSF and one of the study’s lead researchers. Her work supports the idea that microglial function, not just plaque amount, affects how badly someone suffers from Alzheimer’s.

The team confirmed their findings using not just mouse brains, but also human embryonic stem cells turned into microglia. These lab-grown cells behaved the same way: with ADGRG1, they eagerly consumed amyloid beta. Without it, they barely reacted.

The results could have big implications for future Alzheimer’s therapies. Since ADGRG1 is a G protein-coupled receptor, it could be an ideal drug target. These types of receptors already make up a large share of current medicines, treating everything from allergies to heart disease.

Developing drugs that boost ADGRG1 activity could help microglia function better in people with Alzheimer’s, possibly slowing or even stopping the disease. “Some people are lucky to have responsible microglia,” Piao said. “But this discovery creates an opportunity to develop drugs to make microglia effective against amyloid-beta in everyone.”

While more research is needed, especially in humans, this work highlights the promise of targeting microglial pathways. Instead of trying to destroy amyloid plaques directly, future therapies might focus on helping the brain’s own immune cells do the work.

Microglia have long been misunderstood. At first, scientists thought they caused more harm than good by triggering inflammation in the brain. But now, it’s becoming clear that their role is more complex. They can be both protectors and aggressors—depending on how they’re activated.

In the case of Alzheimer’s, the right activation makes all the difference. By switching on the MYC pathway through ADGRG1, microglia can enter a protective mode. They boost their ability to clean up waste, repair damage, and support neurons. The study shows that the microglial state is key to fighting neurodegeneration.

This deeper understanding of microglial behavior is changing the direction of Alzheimer’s research. It shows that genetics alone do not determine disease severity. Instead, how microglia respond to those genetic risks—especially through pathways like ADGRG1-MYC—can shape the brain’s resilience. The more researchers learn about these immune cells, the better they can guide future treatments.

Research findings are available online in the journal Neuron.

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