Peter Searson is leading a Johns Hopkins University team that is unravelling how Alzheimer's and other diseases disrupt the blood-brain barrier, the complex interface that allows or blocks the passage of substances into the brain.
"The blood-brain barrier is a security system that enables the brain to function in a tightly controlled biochemical environment," says Searson, a core researcher in the Institute for NanoBioTechnology and a professor in the Department of Materials Science and Engineering. "By selectively transporting nutrients and other key molecules into the brain, the blood-brain barrier protects the brain, preventing entry of toxins, pathogens, and other molecules that could disrupt normal signaling. This specialized barrier is essential for overall brain health."
Video credit: Aubrey Morse / Johns Hopkins University
Primarily funded by the National Institutes of Health, Searson leads a team using stem cell technology to incorporate human cells into replicas of the small blood vessels in the brain. Like many research efforts across the country, Searson's work faces growing uncertainty around future funding as federal budgets tighten and priorities shift.
In response to a new NIH initiative emphasizing human models that was started in the spring of 2025, Searson's lab is developing tissue-engineered models to study the physiological and pathological responses to chemical, physical, and biological changes associated with neurodegenerative diseases, stroke, aging, and infectious diseases.
Since the blood-brain barrier is critical for normal brain function, its disruption can have a profound effect on brain health. The blood-brain barrier is subjected to stressors from a wide range of sources which can lead to brain pathologies. Examples of stressors include hypertension, poor blood flow, inflammation, and depression.
In mild cases of disruption, molecules from blood in circulation can leak into the brain. This could be reversible and may be localized to specific regions of the brain, but in more severe cases, both molecules and cells in blood can enter the brain, resulting in microbleeds and hemorrhage.
Disruption of the blood-brain barrier is increasingly recognized as a major contributor to a wide range of seemingly unrelated diseases and conditions, including Alzheimer's disease, obesity, chronic pain, traumatic brain injury, and multiple sclerosis. Because it regulates a variety of processes, there are many mechanisms of disruption that can affect the brain in different ways. Furthermore, its ability to repair itself is dependent on the mechanism and magnitude of dysfunction.
"In many diseases of the brain, there are multiple risk factors that can drive different mechanisms of dysfunction. That's one of the things we're trying to untangle: How does a specific risk factor affect the blood-brain barrier?" Searson says.
To figure out how it becomes disrupted and fix it, Searson's lab is using its models to study blood-brain barrier injury and healing and how this is relevant to human disease. They can also genetically engineer the cells to harbor mutations associated with brain diseases, allowing them to study treatments.
Image credit: Will Kirk / Johns Hopkins University
"By observing these microvessels on a microscopic level, we can see how they can mimic responses in the human brain. By replicating the effects of stressors such as inflammation or vessel narrowing, we are deconvoluting how stress causes blood-brain barrier disruption," Searson says.
Normal aging also results in low levels of blood-brain barrier disruption. Searson and his lab are studying how age-related changes in the concentration of blood proteins affect the blood-brain barrier. This work could lead to targeted therapies to slow vascular aging and prevent age-related neurodegenerative diseases.
"Because the blood-brain barrier is so effective, apart from a few very small molecules, it's almost impossible to get drugs into the brain," Searson says. "A major challenge in treating diseases of the brain is getting drugs across the blood-brain barrier."
Searson participated in the Adult Brain Tumor Consortium's Workshop to help identify better strategies to assess the ability of candidate drugs to cross the blood-brain barrier. The models developed in the Searson Lab were used by the consortium to test strategies for delivering drugs or genes to the brain via the blood-brain barrier.
