Researchers may have unlocked the blood-brain barrier
Date:
March 16, 2022
Source:
Yale University
Summary:
The brain is composed of billions of neurons -- vulnerable cells
that require a protective environment to function properly. This
delicate environment is protected by 400 miles of specialized
vasculature designed to limit which substances come into
contact with the brain. This blood- brain barrier is essential
for protecting the organ from toxins and pathogens. But it also
blocks the passage of therapeutic drugs.
FULL STORY ==========================================================================
The brain is composed of billions of neurons -- vulnerable cells that
require a protective environment to function properly. This delicate environment is protected by 400 miles of specialized vasculature
designed to limit which substances come into contact with the brain. This blood-brain barrier is essential for protecting the organ from toxins
and pathogens. But in the context of neurological disease, the barrier
"becomes your worst enemy," says Anne Eichmann, PhD, Ensign Professor of Medicine (Cardiology) and professor of cellular and molecular physiology,
as it also blocks the passage of therapeutic drugs.
==========================================================================
For years, it has been the goal of neuroscientists and vascular biologists alike to find the magic bullet for temporarily opening and resealing
the barrier for drug administration. Now, Eichmann's team has developed
an antibody as a tool for opening the blood-brain barrier for a couple
of hours at a time, allowing for the delivery of drugs to a diseased
brain. The team published its findings in Nature Communications on
March 4.
"This is the first time we've figured out how to control the blood-brain barrier with a molecule," says Eichmann, who is the senior author of
the study.
The development and maintenance of the blood-brain barrier are dependent
on what is called the Wnt signaling pathway, which regulates a number
of crucial cellular processes. Eichmann's team sought to figure out
whether this pathway could be modulated to open the barrier "on-demand."
When Kevin Boye', a postdoctoral associate at Yale and first author of the study, joined Eichmann's lab in 2017, he chose to study a molecule known
as Unc5B, an endothelial membrane receptor expressed in the endothelial
cells of capillaries. He found that if he knocked out this receptor
in mice, they died early in their embryonic development because their vasculature failed to form properly, indicating that it was an important molecule in vascular development.
He also discovered that a protein known as Claudin5 -- which is important
for creating the tight junctions between the endothelial cells of the blood-brain barrier -- was also significantly reduced. This made the team realize that the receptor could be important in maintaining this barrier.
There was previously no known link between Unc5B and the Wnt signaling
pathway.
Through this new study, the team figured out that the Unc5B receptor
controls the pathway, functioning as an upstream regulator.
Boye' then went a step further and took the receptor out in adult mice
with an already established blood-brain barrier, and found that the
barrier remained open in the absence of the receptor. Next, he wanted
to determine which ligands -- which bind to receptors and send signals
between or inside cells -- were responsible for the barrier effect. He discovered that one ligand, Netrin-1, also caused a blood-barrier defect
when it was removed.
Next, the team developed an antibody that could block Netrin-1 from
binding to its receptor. Upon injecting the antibody, the team was able
disrupt the Wnt signaling pathway, causing the blood-brain barrier to
open temporarily on demand.
"It was quite a fascinating journey, especially the development of
our blocking antibodies," says Boye'. "And to see that we can open the blood-brain barrier in a very time-sensitive fashion to promote drug
delivery." Because the blood-brain barrier blocks entry to all but a tiny subset of small molecules, neurological conditions such as Alzheimer's, multiple sclerosis, brain tumors, and depression are exceedingly difficult
to treat. Having control over the barrier will be helpful for future
drug delivery ventures. The team has not yet identified any potential complications, but plans to evaluate the efficacy and potential toxicity
of the antibody in later research.
"This paves the way to more interesting basic research around how the
body builds such a tight barrier to protect its neurons and how can
it be manipulated for drug delivery purposes," says Eichmann. "And
then there's also potential to use this as a delivery platform for
drugs to penetrate into the brain." In future studies, the team hopes
to understand how to apply its findings to chemotherapy delivery for
treating brain tumors. They are also currently working to see if they
can apply their antibody to other regions of the central nervous system
outside of the brain.
========================================================================== Story Source: Materials provided by Yale_University. Original written
by Isabella Backman.
Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Kevin Boye', Luiz Henrique Geraldo, Jessica Furtado, Laurence
Pibouin-
Fragner, Mathilde Poulet, Doyeun Kim, Bryce Nelson, Yunling Xu,
Laurent Jacob, Nawal Maissa, Dritan Agalliu, Lena Claesson-Welsh,
Susan L.
Ackerman, Anne Eichmann. Endothelial Unc5B controls blood-brain
barrier integrity. Nature Communications, 2022; 13 (1) DOI:
10.1038/s41467-022- 28785-9 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220316132708.htm
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