• Researchers may have unlocked the blood-

    From ScienceDaily@1:317/3 to All on Wed Mar 16 22:30:42 2022
    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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