Tearing down the [Blood Brain Barrier] WallEver wonder why you don’t see too many illnesses that affect the brain directly? You can give your head a nice pat and congratulate the blood brain barrier for keeping the bad out and letting the good in. Unfortunately the blood brain barrier can be, well a barrier, or more like a bouncer– especially when it comes to new drugs that could potentially help treat issues with the brain.
The blood-brain barrier helps that finicky brain of yours maintain the delicate environment that it needs to thrive. There’s just one problem: The barrier is so good at what it does, it won’t let medicines pass through. Like most things with the brain, we don’t know enough about it to control it for our benefit.
Thankfully that is changing, now a team from Harvard Medical School has identified a gene in mice that may be responsible for limiting the barrier’s permeability—and the molecule it produces [MFSD2A for those interested] works in a way few researchers expected.
“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, 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 at understanding, or manipulating the blood-brain barrier function, have focused on the seals that prevent all but a few substances from squeezing between barrier cells. Professor Gu and her team discovered that MFSD2A appears to instead affect a second barrier-crossing mechanism that researchers gave little thought, transcytosis. [Loony Hint: Transcytosis is a process where substances are transported through the barrier cells in bubbles called vesicles, think Wizard of Oz style].
Transcytosis occurs frequently at other sites in the body, but is normally suppressed at the blood-brain barrier. MFSD2A may be one of the suppressors. “It’s exciting because this is the first molecule identified that inhibits transcytosis,” said Gu. “It opens up a new way of thinking about how to design strategies to deliver drugs to the central nervous system.”
The studies were done on mice, but MFSD2A has a human equivalent, which is exciting because blocking its activity in people could allow doctors to open the blood-brain barrier briefly [and more important, selectively] to let in drugs to treat life-threatening conditions such as brain tumors and infections.
Conversely, because researchers have begun to link blood-brain barrier degradation to several brain diseases, boosting MFSD2A could allow doctors to strengthen the barrier and perhaps alleviate diseases such as Alzheimer’s, amyotrophic lateral sclerosis [ALS] and multiple sclerosis. The findings may also have implications for other areas of the body that rely on transcytosis too, such as the eyes or kidneys for example.
The team also studied 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 Professor Gu’s 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.
“In addition to MFSD2A, there may be several other molecules on the list that will be good drug targets,” said Gu. “The key here is we are gaining tools to manipulate transcytosis either way: opening or tightening.”
Better understanding and potentially being able to manipulate the molecular underpinnings of transcytosis could aid in the study and treatment of diseases in tissues beyond the brain, from the intestines and how they absorb nutrients, to the kidneys which is busy filtering waste.
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.
How cool is that?
Know more about the blood brain barrier than what was covered here? You probably want the full article then, which can be found — here!
Ben-Zvi A., Lacoste B., Kur E., Andreone B.J., Mayshar Y., Yan H. & Gu C. (2014). Mfsd2a is critical for the formation and function of the blood–brain barrier, Nature, DOI: 10.1038/nature13324