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May 15, 2014

Breaking through the Blood-Brain Barrier

Breaking through the Blood-Brain Barrier

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  • Researchers from the Harvard Medical School (HMS) have identified a gene in mice, Mfsd2a, and the molecule (Mfsd2a) it produces, that may be responsible for limiting the blood-brain barrier's permeability.

    The barrier, which also operates in people, helps maintain the delicate environment that allows the human brain to thrive. There's just one problem: It is so discerning that it won't let medicines pass through. Researchers haven't been able to coax it to open up because they don't know enough about how the barrier forms or functions. But because Mfsd2a has a human equivalent, blocking its activity in people could allow doctors to open the blood-brain barrier briefly and selectively to let in drugs to treat life-threatening conditions such as brain tumors and infections.

    The Harvard study (“Mfsd2a is critical for the formation and function of the blood–brain barrier”) is published in Nature.

    “Right now, 98 percent of small molecule drugs and 100 percent of large molecule drugs and antibodies can't get through the blood-brain barrier,” said Chenghua Gu, Ph.D., associate professor of neurobiology at HMS and senior author of the study. “Less than 1 percent of pharmaceuticals even try to target the barrier, because we don't know what the targets are. Mfsd2a could be one.”

    Most attempts to understand and manipulate blood-brain barrier function have focused on tight junctions, seals that prevent all but a few substances from squeezing between barrier cells. Dr. Gu and her team discovered that Mfsd2a appears to instead affect a second barrier-crossing mechanism that has received much less attention, transcytosis, a process in which substances are transported through the barrier cells in vesicles. Transcytosis occurs frequently at other sites in the body but is normally suppressed at the blood-brain barrier (BBB). Mfsd2a may be one of the suppressors.

    “[We found that a]…super family domain containing 2a (Mfsd2a) is selectively expressed in BBB-containing blood vessels in the CNS. Genetic ablation of Mfsd2a results in a leaky BBB from embryonic stages through to adulthood, but the normal patterning of vascular networks is maintained,” wrote the scientists. “Electron microscopy examination reveals a dramatic increase in CNS-endothelial-cell vesicular transcytosis in Mfsd2a−/− mice, without obvious tight-junction defects. Finally we show that Mfsd2a endothelial expression is regulated by pericytes to facilitate BBB integrity. These findings identify Mfsd2a as a key regulator of BBB function that may act by suppressing transcytosis in CNS endothelial cells. Furthermore, our findings may aid in efforts to develop therapeutic approaches for CNS drug delivery.”

    “It's exciting because this is the first molecule identified that inhibits transcytosis,” said Dr. Gu. “It opens up a new way of thinking about how to design strategies to deliver drugs to the central nervous system.”

    Conversely, because researchers have begun to link blood-brain barrier degradation to several brain diseases, boosting Mfsd2a (the gene) or Mfsd2a (the protein) could allow doctors to strengthen the barrier and perhaps alleviate diseases such as Alzheimer's, amyotrophic lateral sclerosis, and multiple sclerosis. The findings may also have implications for other areas of the body that rely on transcytosis, such as the retina and kidney.

    The team also began to study the relationship between the cortical endothelial cells and another contributor to the blood-brain barrier, cells called pericytes. So far, they have found that pericytes regulate Mfsd2a. Next, they want to learn what exactly the pericytes are telling the endothelial cells to do. Other future work in the Gu lab includes testing the dozen other potential molecular players and trying to piece together the entire network that regulates transcytosis in the blood-brain barrier.

    Being able to open and close the blood-brain barrier also promises to benefit basic research, enabling scientists to investigate how abnormal barrier formation affects brain development and what the relationship may be between barrier deterioration and disease.


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