A new method to map proteins on blood vessel walls has revealed key regulators of the blood-brain barrier, opening possibilities for treating neurological disease and improving drug delivery to the brain.
Getting into the human brain is harder than getting past the toughest nightclub bouncer. For decades, that has been a major obstacle for doctors trying to treat neurological diseases.
Now, researchers have developed a powerful new way to study the brain’s gatekeeper — the blood-brain barrier — and have uncovered two molecular pathways that help decide what gets in and what stays out.
A team led by Jiefu Li, a group leader at the Howard Hughes Medical Institute’s Janelia Research Campus, created a method to label and catalog all the proteins that line the inside surface of blood vessels, known as the luminal surface. Working with the Proteomics Platform at the Broad Institute, they used this approach to map the protein landscape of brain blood vessels across development, adulthood and aging.
Their findings, published in the journal Science, identify two proteins, SLC7A1 and HYAL2, that help maintain the integrity of the blood-brain barrier. When these proteins are lost in laboratory models, the barrier becomes leaky.
That discovery could eventually help scientists design better ways to deliver drugs to the brain and understand what goes wrong in conditions such as multiple sclerosis, encephalitis and dementia, where the barrier is often disrupted.
Li noted that, at its core, the work is about learning how to control a crucial biological checkpoint.
“Understanding how the blood-brain barrier works, particularly figuring out the molecular targets that you can play with to open and close the barrier, will provide new possibilities for drug delivery,” Li said in a news release.
A new window on blood vessel “skin”
The blood-brain barrier is part of the body’s vascular system, the network of blood vessels that carries oxygen, nutrients, hormones, immune cells and waste products to and from organs. The luminal surface of these vessels is the first point of contact between the blood and surrounding tissues — like the inner lining of a pipe.
Proteins embedded in this inner lining act as gatekeepers, selectively transporting nutrients, signaling molecules and immune cells from the bloodstream into organs, including the brain.
“So basically, everything in the circulating blood, if they want to have an exchange with the organ, they need to pass through this interface,” Li added.
Until now, getting a complete picture of all the proteins on this inner surface across the entire vascular system has been extremely challenging. Li’s team set out to change that by developing a labeling strategy that tags luminal proteins in living tissue so they can be isolated and analyzed.
The method is designed to be both comprehensive and practical, giving researchers a way to see which proteins are present on blood vessel walls in different organs and at different life stages.
“This will allow us to say: we know that the vasculature system is doing different things in different organs and it relies on this luminal surface, but how does that happen? What are the molecular players there?” added Li.
Following the barrier across the lifespan
Using their new technique, the researchers focused on the brain’s vasculature, which forms a central part of the blood-brain barrier. They examined how the set of luminal proteins changes from early development through adulthood and into old age.
As the brain matured, they observed a decline in proteins involved in building new blood vessels and transporting molecules. In older brains, they saw shifts in proteins linked to blood vessel stiffness and reduced adaptability — changes that may relate to age-associated declines in brain health.
To move beyond cataloging and into function, the team turned to viral tools developed by Viviana Gradinaru, an investigator at HHMI and the Lois and Victor Troendle Professor of Neuroscience and Biological Engineering at California Institute of Technology. These tools allowed them to manipulate specific proteins in the brain vasculature of laboratory models and see how the blood-brain barrier responded.
Through this combination of mapping and functional tests, the researchers pinpointed SLC7A1 and HYAL2 as key regulators of barrier integrity. One of the proteins is especially active during development, while the other is present throughout life, and each is tied to a distinct cellular process that helps keep the barrier intact.
“What we know now is that we have two new pathways, potentially, to open the blood-brain barrier and to inform some therapeutic developments,” Li added.
Opening the door to new therapies
The blood-brain barrier is essential for protecting the brain from toxins and infections, but its selectivity also blocks many potentially helpful drugs, including treatments for Alzheimer’s and Parkinson’s disease. Researchers have long sought ways to temporarily and safely open the barrier to let medicines through, without causing lasting damage.
By revealing specific proteins and pathways that influence how tight or leaky the barrier is, Li’s work offers new molecular targets that drug developers might one day be able to modulate.
Beyond the brain, the method has broader implications. Because it can be applied to the entire vascular system, scientists can use it to study how blood vessels in different organs specialize and how those specializations change in disease.
The study also delivers a rich dataset: a detailed inventory of luminal proteins in brain blood vessels from development through aging. That resource, along with the labeling technique itself, is freely available for other researchers to build on.
“This method solves an important need but it’s also a very easy-to-use method so everyone can use it,” Li added.
For students and early-career scientists, the work highlights how advances in basic tools — in this case, a better way to see the “skin” of blood vessels — can unlock new questions across neuroscience, immunology and drug development.
The brain’s bouncer is not just a wall; it is a dynamic, protein-studded interface that changes over time and can be pushed off balance in disease. With this new vascular map and method in hand, researchers now have a clearer view of the people on the guest list — and a starting point for learning how to adjust the rope.
Source: Howard Hughes Medical Institute