Study reveals the surprising role of omega-3 fatty acids in keeping the blood-brain barrier closed

May 4, 2017
Normal brain blood vessels completely contain a fluorescent dye (left). Vessels without the lipid transport protein Mfsd2a show a leaky blood-brain barrier. Credit: Gu Lab/Harvard Medical School

Already extolled 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 in vesicles, or small bubbles. They found that the formation of these vesicles is inhibited by the lipid composition of in the central nervous system, which involves a balance between and other lipids maintained by the lipid transport protein Mfsd2a.

While the 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.

"This study presents the first clear molecular mechanism for how low rates of transcytosis are achieved in central nervous system blood vessels to ensure the impermeable nature of the blood-brain barrier," Gu said. "There is still a lot we do not know about how the barrier is regulated. A better understanding of the mechanisms will allow us to begin to manipulate it, with the goal of getting therapeutics into the brain safely and effectively."

The blood-brain barrier is composed of a network of 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.

Unfavorable conditions

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.

"We think that by incorporating DHA into the membrane, Mfsd2a is fundamentally changing the composition of the membrane and making it unfavorable for the formation of these specific type of caveolae," Andreone said. "Even though we observed low rates of vesicle formation and transcytosis in blood-brain barrier cells decades ago, this is the first time that a cellular mechanism can explain this phenomenon."

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.

"Many of the drugs that could be effective against diseases of the brain have a hard time crossing the blood-brain barrier," Gu said. "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."

Explore further: Cross-cell transport bears unexpected responsibility for sealing blood-retinal barrier

Related Stories

Cross-cell transport bears unexpected responsibility for sealing blood-retinal barrier

March 24, 2017
A cellular trafficking system called transcytosis may actually do most of the work in controlling the permeability of the barrier between the blood and the central nervous system, according to new research conducted in mice ...

Possible new plan of attack for opening and closing the blood-brain barrier

May 14, 2014
Like a bouncer at an exclusive nightclub, the blood-brain barrier allows only select molecules to pass from the bloodstream into the fluid that bathes the brain. Vital nutrients get in; toxins and pathogens are blocked. The ...

What is the blood-brain barrier and how can we overcome it?

April 6, 2017
The brain is precious, and evolution has gone to great lengths to protect it from damage. The most obvious is our 7mm thick skull, but the brain is also surrounded by protective fluid (cerebrospinal – of the brain and spine) ...

Asian family research answers questions on fatty acid in brain

May 25, 2015
New research conducted in a rural community in Pakistan highlights the crucial role that essential fatty acids play in human brain growth and function.

Study IDs new cause of brain bleeding immediately after stroke

April 17, 2014
By discovering a new mechanism that allows blood to enter the brain immediately after a stroke, researchers at UC Irvine and the Salk Institute have opened the door to new therapies that may limit or prevent stroke-induced ...

Recommended for you

The neural codes for body movements

July 21, 2017
A small patch of neurons in the brain can encode the movements of many body parts, according to researchers in the laboratory of Caltech's Richard Andersen, James G. Boswell Professor of Neuroscience, Tianqiao and Chrissy ...

Faulty support cells disrupt communication in brains of people with schizophrenia

July 20, 2017
New research has identified the culprit behind the wiring problems in the brains of people with schizophrenia. When researchers transplanted human brain cells generated from individuals diagnosed with childhood-onset schizophrenia ...

Scientists reveal how patterns of brain activity direct specific body movements

July 20, 2017
New research by Columbia scientists offers fresh insight into how the brain tells the body to move, from simple behaviors like walking, to trained movements that may take years to master. The discovery in mice advances knowledge ...

Scientists discover combined sensory map for heat, humidity in fly brain

July 20, 2017
Northwestern University neuroscientists now can visualize how fruit flies sense and process humidity and temperature together through a "sensory map" within their brains, according to new research.

Team traces masculinization in mice to estrogen receptor in inhibitory neurons

July 20, 2017
Researchers at Cold Spring Harbor Laboratory (CSHL) have opened a black box in the brain whose contents explain one of the remarkable yet mysterious facts of life.

Speech language therapy delivered through the Internet leads to similar improvements as in-person treatment

July 20, 2017
Telerehabilitation helps healthcare professionals reach more patients in need, but some worry it doesn't offer the same quality of care as in-person treatment. This isn't the case, according to recent research by Baycrest.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

PPihkala
not rated yet May 05, 2017
I read this study the other way around: In order to have working BBB one needs to have adequate intake of DHA, ie omega-3 acids. Maybe the current high rates of Alzheimer's are indicative of low omega-3 intake in the sufferers. And because omega-3's have low or none of adverse effects, we should make sure people get enough of them, especially if they have brain problems.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.