New research in mice and zebrafish has uncovered the genetic signal needed to form and maintain the blood-brain barrier. The discovery could let scientists control the barrier’s permeability, providing a more effective way of delivering medicines to the brain to treat stroke, neurodegenerative and psychiatric diseases, and cancer.
The blood-brain barrier (BBB) is a tightly interlaced system of specialized cells that creates a layered semi-permeable membrane that serves a dual purpose: it protects against toxins or pathogens entering the brain from the bloodstream, while at the same time allowing through vital nutrients.
But the BBB’s protective function can hinder effective drug delivery to the brain to treat cancer, stroke or neurodegenerative diseases like Parkinson’s or Alzheimer’s. Over the years, different methods have been developed to increase the permeability, or leakiness, of the BBB to enable the delivery of drug treatments, including using magnetic nanoparticles, ultrasound, and engineered fat cells.
Now, a new study by researchers at Harvard Medical School has identified the gene that produces the signal necessary for the development and maintenance of the BBB and may have uncovered a way to control the barrier’s permeability.
Researchers have long known that the BBB’s permeability was controlled by cells in the surrounding environment, but the genes in those cells remained unknown. It wasn’t until the researchers in the current study started examining the BBB in zebrafish that questions started to be answered.
In previous studies of the transparent zebrafish, the researchers discovered a gene called mfsd2aa that, when mutated, caused the BBB to become leaky across the entire brain. But, in some fish, the barrier was permeable only in the forebrain and midbrain, not the hindbrain.
“This observation led me down a rabbit hole of finding the gene that causes the blood-brain barrier to become regionally permeable,” said Natasha O’Brown, lead author of the study.
In the current study, the researchers conducted further experiments on zebrafish and mice. They found that the region-specific breakdown of the BBB was linked to a mutation in the spock1 gene, which is expressed in nerve cells throughout the retina, brain, and spinal cord but not in the cells that make up the BBB.
They observed that the animals with the spock1 mutation had more vesicles in their endothelial cells, key constituents of the BBB. Vesicles are bubble-like membranes that store and transport cellular products and can carry large molecules across the barrier. They also had a smaller basement membrane, the network of proteins found between endothelial cells and pericytes, cells important for blood vessel formation and the maintenance of the BBB.
RNA analysis revealed that spock1 altered the gene expression in endothelial cells and pericytes in the BBB but not in other types of brain cells. When zebrafish brains were injected with human Spock1 protein, the endothelial cells and pericytes were repaired at a molecular level, restoring around 50% of BBB function. Based on this discovery, the researchers concluded that the Spock1 protein produced by neurons initiates the formation of the BBB during embryonic development and helps maintain it throughout adulthood.
“Spock1 is a potent secreted neural signal that is able to promote and induce barrier properties in these blood vessels; without it, you don’t get a functional blood-brain barrier,” O’Brown said. “It’s like a spark on a gas stove, providing a cue that tells the barrier program to turn on.”
The researchers say their study provides a more complete picture of BBB permeability. It opens the door to developing therapeutics that target spock1, potentially improving the treatment of neurodegenerative disorders such as Parkinson’s and Alzheimer’s and psychiatric disorders.
“This isn’t the first neural signal scientists have found, but it is the first signal from neurons that specifically seems to regulate barrier properties,” said O’Brown. “I think this makes it a potent tool to try and toggle the switch.”
The researchers will next look at how different pericytes are affected by spock1 signaling. And they’d like to see whether administering spock1 can counter the effects of stroke on the BBB.
The study was published in the journal Developmental Cell.
Source: Harvard Medical School