SAN FRANCISCO—Your brain is protected by the blood-brain barrier—a network of cells in the brain's blood vessels that serves as a border between the brain and the rest of your bloodstream. But it's not just a barrier; it's a sophisticated interface that shuttles specific molecules between the blood and the brain to keep your brain healthy.
Working in mice, Gladstone Investigator Andrew Yang, PhD, and his team have created the first atlas of proteins in the bloodstream that are transported across the blood-brain barrier and into the brain. Reported in the journal Cell, the atlas contains 92 proteins so far, and it's already pointing toward potential new strategies for treating neurodegenerative conditions such as Alzheimer's disease.
"For a century, we've treated the blood-brain barrier as a simple physical boundary protecting the brain from toxins," says Yang, who led the study. "We're finding that it's an intelligent interface that plucks the right proteins in the blood, often from distant parts of the body, and delivers them to the right cell types in the brain. Brain health depends on this sophisticated molecular supply line from the body."
Brain-Body Dialogue
Multiple organs in the body, such as the liver and kidney, release different proteins into the blood at different times. This means the specific mix of protein types in blood plasma—the liquid portion of the blood—can relay important information to the brain about the current state of the body. But with the blood-brain barrier, which of these proteins can the brain sense?
To answer this question, Yang's team wanted to track which specific blood plasma proteins are shuttled into the brains of mice. But existing methods were inefficient and risked interfering with the body's processes.
So, they leveraged Nobel Prize-winning protein-labeling chemistry to develop a more efficient way to track the transit of proteins from the body into the brain, without disrupting their biology. They used this method to label the full repertoire of mouse blood proteins, which they injected back into the bloodstreams of mice. Then, they examined the brain tissue to see which labeled proteins had crossed the blood-brain barrier.
Of the 861 proteins the scientists tracked, the blood-brain barrier only allowed 92 to enter the brain. Most of these proteins were produced in distant parts of the body, especially the liver. The findings suggest that the blood-brain barrier acts as a gatekeeper, using specialized receptors to identify and transport specific plasma proteins from the body into the brain.
"We think of blood proteins as messengers carrying signals from distant body parts, and the cells of the blood-brain barrier import only the ones the brain really needs," says Haoyue Zhou, PhD, a postdoctoral scholar in Yang's lab and first author of the paper.
The team also found that, once inside the brain, different proteins are directed to specific types of brain cells, where they carry out specialized functions.
"It's like a molecular ZIP code system that helps each protein reach its intended destination," Zhou says.
For example, a protein made in the liver travels to the brain to support cells known as astrocytes. Once in the brain, the protein—known as apolipoprotein A1, or APOA1—activates a pathway that maintains healthy connections between neurons. Failure of this pathway has previously been linked to a higher risk of Alzheimer's disease, suggesting that signals from elsewhere in the body may play an important role in brain function.
"We find the blood-brain barrier is a very dynamic delivery system that seems to connect the brain with the rest of the body to promote brain health," Zhou says. "But that's just the beginning of the story."
A Blueprint for New Treatments
To uncover more of the story, the team wanted to find out what happens to this delivery system in disease.
Scientists have long known that as Alzheimer's disease progresses, the blood-brain barrier physically breaks down and begins leaking harmful proteins into the brain. Yang's team discovered that a different problem arises even earlier.
Using their labeling technique in a mouse model of Alzheimer's, they found that before the barrier breaks down, it stops importing protective proteins like APOA1 into the brain. This change was accompanied by an erosion of neuronal connections, behavioral changes, and other early signs of the disease.
"Before the barrier starts leaking harmful proteins into the brain, it stops letting the beneficial ones through," Zhou says. "The brain's supply line from the body starts to fail."
These findings raised an important question: Could increasing the supply of APOA1 help counter signs of Alzheimer's disease? To find out, the researchers studied mouse models engineered to produce extra APOA1 in the liver. Indeed, as more APOA1 crossed the blood-brain barrier and entered the brain, the mice showed fewer signs of Alzheimer's disease.
Overall, this study suggests that the blood-brain barrier acts not only as a protective shield, but also as a delivery system, transporting beneficial proteins from the bloodstream into the brain. The blood-brain barrier's delivery function may be a critical early failure point in Alzheimer's and other neurodegenerative diseases.
"Alzheimer's disease may not start entirely inside the brain; It may start when the brain's supply line from the body is severed," Yang says. "If that's right, we may be able to fight this disease from outside the brain, by restoring what the brain has lost."
The work by Yang's team points to potential new treatment strategies. One possibility is boosting the production of beneficial proteins in other organs such as the liver, so that more can reach the brain. Another is harnessing the brain's natural "ZIP code" system to deliver therapies directly to specific types of brain cells.
The group is already pursuing yet another promising strategy: harnessing the blood-brain barrier's unexpectedly rich transport machinery to help drugs reach the brain more efficiently, especially in neurodegenerative disease.
"We now have a map of the proteins the brain needs from the body and the transport system that delivers them," Yang says. "We are excited to translate this blueprint into new therapies for Alzheimer's that work from the outside-in, and into next-generation blood-brain barrier shuttles to deliver powerful medicines into the brain."
