May 30, 2017Quiz
Every thought and action requires precise communication between the nerve cells of the brain and the cells involved in the action. For these messages to be successfully transmitted and received, the surrounding environment needs to be stable. The brain separates itself from the natural chemical fluctuations that occur in the body by elaborate means called the blood brain barrier. The brain is the only organ known to have its own security system, a network of blood vessels that allows the entry of essential nutrients while blocking other substances. Unfortunately, this barrier is so effective at protecting against the passage of foreign substances that it often prevents life-saving drugs from being able to repair the injured or diseased brain. New studies are guiding researchers toward creative ways to open this barrier and trick it into allowing medicines to enter.
The brain's blood vessels are lined with endothelial cells that are wedged tightly together creating a nearly impermeable boundary between the brain and bloodstream. The blood-brain barrier (BBB) is a diffusion barrier, which impedes influx of most compounds from blood to brain. Three cellular elements of the brain microvasculature compose the BBB-endothelial cells, astrocyte end-feet, and pericytes (PCs). Tight junctions (TJs), present between the cerebral endothelial cells, form a diffusion barrier, which selectively excludes most blood-borne substances from entering the brain. Astrocytic end-feet tightly ensheath the vessel wall and appear to be critical for the induction and maintenance of the TJ barrier, but astrocytes are not believed to have a barrier function in the mammalian brain. Dysfunction of the BBB, for example, impairment of the TJ seal, complicates a number of neurologic diseases including stroke and neuroinflammatory disorders. A paucity of TJs or PCs, coupled with incomplete coverage of blood vessels by astrocyte end-feet, may account for the fragility of blood vessels in the GM of premature infants.
Many researchers are concerned with the pathogenesis of increased BBB permeability in hypoxia-ischemia and inflammatory mechanisms involving the BBB in septic encephalopathy, HIV-induced dementia, multiple sclerosis, and Alzheimer disease. Already recognized for their health benefits as a food compound, omega-3 fatty acids now appear to also play a critical role in preserving the integrity of the blood-brain barrier, which protects the central nervous system from blood-borne bacteria, toxins and other pathogens, according to new research from Harvard Medical School. Reporting in the May 3 issue of Neuron, a team led by Chenghua Gu, associate professor of neurobiology at Harvard Medical School, describes the first molecular explanation for how the barrier remains closed by suppressing transcytosis -- a process for transporting molecules across cells in vesicles, or small bubbles. They found that the formation of these vesicles is inhibited by the lipid composition of blood vessel cells in the central nervous system, which involves a balance between omega-3 fatty acids and other lipids maintained by the lipid transport protein Mfsd2a.
While the blood-brain barrier is a critical evolutionary mechanism that protects the central nervous system from harm, it also represents a major hurdle for delivering therapeutic compounds into the brain. Blocking the activity of Mfsd2a may be a strategy for getting drugs across the barrier and into the brain to treat a range of disorders such as brain cancer, stroke and Alzheimer's. The blood-brain barrier is composed of a network of endothelial cells that line blood vessels in the central nervous system. These cells are connected by tight junctions that prevent most molecules from passing between them, including many drugs that target brain diseases. In a 2014 study published in Nature, Gu and colleagues discovered that a gene and the protein it encodes, Mfsd2a, inhibits transcytosis and is critical for maintaining the blood-brain barrier. Mice that lacked Mfsd2a, which is found only in endothelial cells in the central nervous system, had higher rates of vesicle formation and leaky barriers, despite having normal tight junctions.
In the current study, Gu, Benjamin Andreone, a neurology student at Harvard Medical School, and their colleagues examined how Mfsd2a maintains the blood-brain barrier. Mfsd2a is a transporter protein that moves lipids containing DHA, an omega-3 fatty acid found in fish oil and nuts, into the cell membrane. To test the importance of this function to the barrier, the team created mice with a mutated form of Mfsd2a, in which a single amino acid substitution shut down its ability to transport DHA. They injected these mice with a fluorescent dye and observed leaky blood-brain barriers and higher rates of vesicle formation and transcytosis -- mirroring mice that completely lacked Mfsd2a. A comparison of the lipid composition of endothelial cells in brain capillaries against those in lung capillaries -- which do not have barrier properties and do not express Mfsd2a -- revealed that brain endothelial cells had around two- to five-fold higher levels of DHA-containing lipids. Additional experiments revealed that Mfsd2a suppresses transcytosis by inhibiting the formation of caveolae -- a type of vesicle that forms when a small segment of the cell membrane pinches in on itself. As expected, mice with normal Cav-1, a protein required for caveolae formation, and that lacked Mfsd2a exhibited higher transcytosis and leaky barriers. Mice that lacked both Mfsd2a and Cav-1, however, had low transcytosis and impermeable blood-brain barriers.
By revealing the role of Mfsd2a and how it controls transcytosis in the central nervous system, Gu and her colleagues hope to shed light on new strategies to open the barrier and allow drugs to enter and remain in the brain. They are currently testing the efficacy of an antibody that potentially can temporarily block the function of Msfd2a, and whether caveolae-mediated transcytosis can be leveraged to shuttle therapeutics across the barrier. According to Gu, Many of the drugs that could be effective against diseases of the brain have a hard time crossing the blood-brain barrier, and that suppressing Mfsd2a may be an additional strategy that allows us to increase transcytosis, and deliver cargo such as antibodies against beta-amyloid or compounds that selectively attack tumor cells. If we can find a way across the barrier, the impact would be enormous.
This work was supported by The National Institutes of Health (grants F31NS090669, NS092473), the Mahoney postdoctoral fellowship, the Howard Hughes Medical Institute, the Kaneb Fellowship, Fidelity Biosciences Research Initiative and the Harvard Blavatnik Biomedical Accelerator. Sources: Harvard Medical School: Benjamin J. Andreone, Brian Wai Chow, Aleksandra Tata, Baptiste Lacoste, Ayal Ben-Zvi, Kevin Bullock, Amy A. Deik, David D. Ginty, Clary B. Clish, Chenghua Gu. Blood-Brain Barrier Permeability Is Regulated by Lipid Transport-Dependent Suppression of Caveolae-Mediated Transcytosis. Neuron, 2017; 94 (3): 581 DOI: 10.1016/j.neuron.2017.03.043
BBB Quiz Questions
1. What is blood brain barrier?
2. The BBB is both what? And what?
3. The BBB is a Barrier between what fluid?
4. Brain capillaries create what barrier?
5. The BBB is not truly a what?
6. What role does a membrane play re: the BBB?
7. What is the roll of the endothelial cells in the BBB?
8. Astrocytes hold various roles, mostly supporting neurons. What type of cell are astrocytes.
9. What types of substances are isolated from the brain by the BBB?
10. The brain uses information from the multiple receptors to determine properties of a what?
1. A physiological mechanism that alters the permeability of brain capillaries so that some substances, such as certain drugs, are prevented from entering brain tissue, while other substances are allowed to enter freely.
2. Physical barrier and a system of cellular transport mechanisms.
3. Interstital fluid and the blood around the blood
4. A functional barrier
5. It's not truly a barrier, but actually selective permeability caused by tight junction between endothelial cells
6. A membrane carries and channels select nutrients and molecules across the BBB -Bood brain barrier
7. The endothelial cells control vascular function.
8. Astrocytes are one of six types of star shaped glial cells in the brain and spinal cord. Glial cells are the most abundant cell of the human brain.
9. Toxins and other dangerous substances are kept out of the brain by the BBB.