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    Home > Biochemistry News > Biotechnology News > New research on repairing blood-brain barrier leads to innovative approach to treating multiple brain diseases

    New research on repairing blood-brain barrier leads to innovative approach to treating multiple brain diseases

    • Last Update: 2022-05-24
    • Source: Internet
    • Author: User
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    Neurodegenerative diseases such as traumatic brain injury, stroke, brain tumor or Alzheimer's disease all involve dysfunction of a key player in protecting the brain, the blood-brain barrier (BBB)
    .

    An intact blood-brain barrier acts as a filter between blood and brain tissue, protecting the brain from toxic components in the blood circulation
    .
    When this barrier fails, the "leaked" fluids, molecules and cells alter the environment of the nerve cells, causing the nerve cells to die and the disease to worsen

    .
    Therefore, restoring the damaged blood-brain barrier becomes an important strategy in the treatment of these diseases

    .

    A new study in the top academic journal Science shows an innovative approach to repairing the blood-brain barrier
    .
    In a variety of mouse models, the researchers used an engineered molecule they developed to effectively restore the normal function of the blood-brain barrier and slow the progression of pathology

    .
    This achievement provides new ideas for the treatment of various human diseases related to cerebrovascular defects

    .

    Previous work has found that the early development and maintenance of the blood-brain barrier is regulated by two secreted protein molecules, Wnt7a and Wnt7b
    .
    These two proteins initiate intracellular signaling pathways by binding to the specific receptor Fz protein on the cell surface

    .
    Therefore, from a therapeutic point of view, Wnt7a and 7b are also considered promising to be used for repair when the blood-brain barrier is damaged

    .

    A practical problem with this line of thinking, however, is how to improve specificity
    .
    Because Wnt proteins and their Fz receptors are widely expressed in various cells and tissues, activation of Wnt signaling in other tissues or cells during repair of the blood-brain barrier may pose safety concerns

    .

    To this end, the research team at the ULB Neuroscience Institute in Belgium developed a special engineered Wnt7a protein
    .
    Genetically engineered, this Wnt ligand protein can activate downstream molecular signals specifically targeting endothelial cells that constitute the blood-brain barrier

    .

    ▲ According to the special pattern of Wnt7a activating receptors on vascular epithelial cells, the researchers designed Wnt ligands that specifically target the blood-brain barrier (Image source: Reference [1]

    Specifically, the engineered Wnt7a protein (Wnt7a K190A) differs from native Wnt7a by only one amino acid, but this mutation confers the ability to selectively bind the Gpr124/Reck complex
    .
    When generating cerebral blood vessels and regulating the blood-brain barrier, Wnt7a protein on vascular endothelial cells has an atypical interaction mode with Fz receptor, that is, it binds to the complex formed by Gpr124 and Reck protein on the membrane at the same time

    .
    Based on this finding, engineered Wnt7a could act as a highly specific Gpr124/Reck agonist to reduce its activation of Wnt signaling in other tissues

    .

    Using Xenopus laevis, zebrafish, neonatal mice and other animals as models, the researchers first verified that the mRNA encoding the Wnt7a K190A protein did not cause developmental abnormalities even if it was delivered to animals at high doses, providing a safe treatment for it.
    premise

    .

    Next, the researchers examined the therapeutic potential of Wnt7a K190A in mouse models of brain tumors and ischemic stroke
    .
    Both diseases cause leakage of the blood-brain barrier

    .
    Using an engineered adeno-associated virus (AAV) as a vector, they delivered the gene encoding Wnt7a K190A into mice by intravenous injection

    .

    ▲ Schematic diagram of the research on repairing the blood-brain barrier using the modified Wnt7a (Image source: Reference [1]; Credit: Illustration created with BioRender)

    The experiments showed that mice transplanted with glioblastoma cells also had smaller tumors after restoring Wnt signaling in the vascular endothelium and the properties of the blood-brain barrier
    .
    Stroke mice also benefited from treatment with Wnt7a K190A, with reduced cerebral infarct size and improved blood-brain barrier function compared to control mice

    .
    These results suggest that using this Gpr124/Reck agonist to preserve blood-brain barrier function can alleviate glioblastoma expansion and ischemic stroke infarction

    .

    At the end of the paper abstract, the researchers pointed out that this new type of blood-brain barrier therapy can restore the function of the blood-brain barrier by specifically regulating Wnt signaling, bringing potential new treatments for central nervous system diseases
    .
    The research team said that the effect of this neurovascular therapy will be explored in more brain disease models in the future, and will benefit patients as soon as possible

    .

    References:

    [1] Maud Martin et al.
    , (2022) Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders.
    Science.
    Doi: 10.
    1126/science.
    abm4459

    [2] Andrew McMahon & Justin Ichida (2022) Repairing the blood-brain barrier.
    Science Doi: 10.
    1126/science.
    abn7921

    [3] Method enables blood-brain barrier repair in neurological disorders.
    Retrieved Feb.
    21, 2022 from https://medicalxpress.
    com/news/2022-02-method-enables-blood-brain-barrier-neurological.
    html

    (Original abridged)

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