One of the mantras in neuroscience is that the blood brain barrier (BBB) protects the brain from invaders. But is that really the case? Research shows that lots of things can get through: pathogens like E.coli and P. gingivalis, our own cells, and, of course, various molecules that are present in our blood.
The term BBB was coined by Lewandowsky and co-workers 111 years ago after noticing that injection of dyes in peripheral veins barely leads to any noticeable neurological symptom while the injection of the same dyes directly into the brain leads to profound behavioural and cognitive changes.
Anatomically, the BBB is a complex structure found around the brain, which is made up of a wide range of cells including endothelial cells, Star-shaped glial cells that have a number of functions, inc..., pericytes and a basement membrane, mainly comprised of proteins. Its primary function is to keep things out – unfortunately, often that includes medicines. Recent calculations have shown that only 2% of drugs thought to act on the brain can actually cross the BBB. This estimate does not even take into account volumes: certain drugs not only need to travel across this barrier but need to do so in quantities large enough to exert their action. In other words, it seems that the BBB might also work to keep out the good stuff.
What about pathogens? Pathogens love the brain because it is energy rich. The brain uses around 50% of our carbohydrates which makes it a perfect environment for pathogens’ survival. Pathogens are constantly trying to get in, and nothing shows this more than the fact that there is a multitude of methods that they can use to enter the brain: transcellular The brain and spinal cord. (CNS) penetration – where the microbes cross through the endothelial cells themselves -, paracellular CNS penetration – where microbes pass between the endothelial cells -, and the Trojan Horse method – where microbes infect phagocytes (a type of white blood cell), then tag along when the immune cell enters the brain. This method further shows how the brain is not as sheltered from infection as we once thought.
“Pathogens are constantly trying to get in”
In fact, there is a way to enter the brain by avoiding the BBB altogether. Brains are characterised by the presence of the circumventricular organs which consist of the pineal gland, median eminence, subfornical organs and more. These areas are not covered by the BBB and therefore pathogens can enter straight from the blood. If that was not enough, research shows that microbes can also sneak in through the nose as you breathe every day, traveling along your olfactory nerves before spreading throughout the whole brain.
But what about cells from elsewhere in the body? Can they enter the brain through the BBB? The short answer is yes. It turns out that our brain allows a constant stream of immune cells to enter, leading to a lot of problems. For a long time it was thought that immune cells from outside the brain only entered CNS in diseases like multiple sclerosis, where our own immune system attacks myelin, the fatty layer around neurons that allows for speedy transmission of signals. Or in Alzheimer’s disease where a breakdown of the blood brain barrier lets in an army of inflammatory white blood cells that wreak havoc on your brain.
Like pathogens, molecules also use transcellular and paracellular diffusion to enter the brain. Only a select few substances can enter the brain: small, lipid-soluble, hydrophilic, and non-ionized compounds can enter the brain through diffusion. Nonetheless, the BBB weakens as we age so you would expect less protein to cross into the brain. Studies in mice have shown that the entry of proteins across the brain actually decreases with age. This means that in younger mice more protein is being transported across not less which should be expected. This conundrum can be explained because as non-specific protein transport increases with age, plasma protein transport into the brain decreases with age leading to an overall decrease in the transport across the BBB.
“Nonetheless, the BBB weakens as we age so you would expect less protein to cross into the brain”
Today, we know that the BBB is not fully protective because many of the transport proteins on its surface allow for receptor mediated transport (RMT). Think of RMT like a lock and key: The cargo is the key and the receptor on the cell membrane is the lock. Anything that fits into the lock will be transported across the BBB. This means that the BBB is acting more like a sieve rather than a wall.
The BBB is clearly more permeable than it was thought to be upon its discovery 111 years ago. Finding out exactly how permeable it is will require more research into how it transports proteins, pathogens, and cells. So far, scientists have been concentrating their research on a few types of invaders and proteins. Understanding what cells can pass through will require advanced techniques like RNA sequencing to see what types of immune cells get through. Finally, although current research disproportionately focuses on a small range of pathogens, future work should examine a wider range of organisms to determine how pathogens penetrate the BBB in health and disease. As it turns out, evolution has equipped pathogens, cells and other material with multiple ways to cross the BBB and we are just beginning to shed light on them.
Written by Abdullah Iqbal.
Edited by Sean Noah and Desislava Nesheva. Illustrated by Sumana Shrestha.
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Interested in similar articles? Have a look at our other article on the BBB.
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