Proteins Controlling the Blood–Brain Barrier Change Dramatically With Age
A new proteomics method reveals how the blood–brain barrier matures, ages, and could be therapeutically controlled.
The blood–brain barrier (BBB) acts as a biological wall that protects the brain, while simultaneously blocking 98% of potential neurological drugs.
A new study from Janelia Research Campus and the Broad Institute has used high-resolution proteomics to map this interface in vivo for the first time. The results reveal how the barrier matures and ages, providing a blueprint for manipulating vascular permeability to treat neurodegeneration.
Mapping the blood–brain barrier through in vivo proteomics
Blood vessels are the body’s delivery network; they transport oxygen, nutrients, and immune cells to every organ. However, the brain is a little different.
The brain’s vessels form a highly selective barricade, known as the BBB, which acts as a physical and chemical filter that maintains the brain’s environment. This barrier is the primary interface between the blood and the brain; it must be permeable enough to let nutrients in, yet tight enough to keep toxins and pathogens out. When this wall fails, the results can be devastating, contributing to multiple sclerosis, encephalitis, and various forms of dementia.
The BBB is so effective that it blocks the majority of small-molecule drugs and nearly all large-molecule therapies for Alzheimer’s and Parkinson’s.
“Everything in the circulating blood, if they want to have an exchange with the organ, they need to pass through this interface,” explained senior author Dr. Jiefu Li, a group leader at Janelia Research Campus.
To study this system, researchers need to see the proteins on the inside of the blood vessel wall, also called the luminal surface. Despite their importance, until now, scientists have lacked a way to isolate surface proteins from the luminal surface in a living organism. Previous attempts often required complex genetic modifications or inadvertently labeled proteins deep inside the tissue rather than just the surface.
“Understanding how the BBB 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,” said Li.
“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?” he added.
Uncovering vascular aging with high-resolution proteomics
Li and the team developed a method called WGA-HRP proximity labeling. They used a sugar-binding protein, wheat germ agglutinin (WGA), and linked it to an enzyme called horseradish peroxidase (HRP). Because WGA sticks naturally to the interior of blood vessels, it anchors the enzyme to the luminal surface.
When the researchers then circulate a biotin probe through the blood, the enzyme activates it, tagging every nearby protein with a chemical flag. This allowed the team to use mass spectrometry to identify the proteins specifically located at the vascular interface without disturbing the surrounding brain tissue.
To track these changes over time, the researchers profiled the vascular proteome of mice at three distinct life stages: neonatal (6 days), adult (3 months), and aged (20 months).
The study produced an atlas of over 1,000 proteins that is now open access for the entire scientific community.
The resulting proteomics data revealed a dramatic shift over time. In neonatal stages, the BBB is a hive of activity, packed with proteins that drive the growth of new vessels and the transport of nutrients. As the brain matures into adulthood, these growth signals diminish. By old age, the profile shifts again toward a proinflammatory state, the vessels become physically stiffer and less efficient at adapting to the brain's needs. This transition from a flexible, growth-oriented system to a rigid, inflamed one provides a molecular map of vascular aging.
The study also identified two proteins that act as essential structural anchors. The first, SLC7A1, is a neonatal-specific regulator that works with the NOS3 pathway to maintain the barrier in early life. The second, an enzyme called HYAL2, acted as a universal guardian of the barrier's integrity across all ages.
The NOS3 pathway
The NOS3 pathway (Nitric oxide synthase 3) is a signaling system that regulates blood vessel dilation and maintains the health of the vascular lining by producing nitric oxide.
When the researchers removed these proteins in laboratory models using viral vectors, the barrier became leaky.
New therapeutic targets for blood–brain barrier integrity
The discovery of these molecular switches could change how we treat neurological disease; if HYAL2 or SLC7A1 can be modulated, they could be used to bypass the BBB.
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“What we know now is that we have two new pathways, potentially, to open the blood–brain barrier and to inform some therapeutic developments,” said Li.
This could allow for the targeted delivery of chemotherapy or gene therapies that are currently excluded from the brain. Reinforcing these pathways could also help “plug” the leaks seen in neurodegenerative conditions.
The researchers confirmed WGA-HRP proximity labeling also worked in other organs, such as the kidney and intestine, and in different species, including the northern tree shrew.
“This method solves an important need, but it’s also a very easy-to-use method so everyone can use it,” Li said.
Because it does not require specialized transgenic animals, labs worldwide are now able to map the vascular surfaces of various disease models.
Future work will need to focus on translating these findings into human clinical contexts. Creating similar proteomic maps for human organ-specific vasculature could lead to drugs that only release their dose in specific tissues.
The study provides a massive, open-access resource for the scientific community; by defining the molecular players at the interface of our blood and our brain, scientists are closer to turning a biological wall into a manageable door.
Reference: Zhu Z, Jiang Z, Wang Y, et al. Luminal surface proteome of the brain vasculature uncovers blood-brain barrier regulators. Science. 2026;392(6794):eaea2100. doi: 10.1126/science.aea2100
This article is a rework of a press release issued by Howard Hughes Medical Institute. Material has been edited for length and content.
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