Skip to content

Researchers identify how the blood-brain barrier is maintained to control ‘tight junction’ function.

It has long been known that the brain is protected from alterations elsewhere in the body by a highly regulated gateway known as the blood-brain barrier, which allows only selected molecules to pass through.  In certain diseases, however, such as multiple sclerosis, the barrier can be improperly breached. These ‘leaks’ can allow immune cells and inflammatory molecules to pass through, causing inflammation that may lead to neuronal damage.

Now, in a study from researchers at University of Pennsylvania, McGill University and the University of Montreal has made insights into how the blood-brain barrier, or BBB, is maintained, identifying a protein key to the process. It was also observed in the new study that delivering this protein to mice with the rodent equivalent of MS improved their symptoms.  The study is published in the journal Brain.

In 2011 the team published a study in Science that showed that the protein sonic hedgehog, or Shh, is secreted by central nervous system cells called astrocytes and plays a key role in blood-brain barrier maintenance, in part by preventing immune cells from entering the brain.  However, the researchers still didn’t have a complete picture of the signaling events downstream of Shh that mediated this effect. To learn more, they first used human cells in culture from the blood-brain barrier, called endothelial cells. They found that applying Shh to the cells caused levels of a protein called netrin-1 to rise.

The previous study from the team also found that in mice bred to lack the molecular receptor for Shh, netrin-1 expression was reduced, indicating that netrin-1 expression depends on Shh.  The team state that netrins are best known to play a role in guiding the direction of axon growth as well as morphogenesis and tissue formation.  However, their work suggested a new role for netrin-1 in the blood brain barrier.

Curious as to whether this might influence MS, the current study examined BBB cells from the brains of people who had died from the disease. Normal tissue from these individuals contained low levels of netrin-1, while the diseased lesions in the brain had higher levels. The researchers found similar results in a mouse model of MS called experimental autoimmune encephalomyelitis, or EAE.

Next, the team directly measured netrin-1’s effect on BBB permeability by labeling tracer molecules and found that netrin-1 significantly reduced the movement of molecules across cultures of human BBB endothelial cells. Further experiments showed that netrin regulates this process by promoting the expression of the so-called ‘tight junction’ proteins, which are located between BBB endothelial cells and are responsible for controlling barrier function. The researchers also found that, when in an environment rife with inflammatory signaling molecules, which would normally compromise the integrity of the BBB, netrin-1 had a counteracting effect, preventing disruption to the BBB.

In mice bred to lack netrin-1, it was observed that proteins normally found in the blood accumulated in the animals’ brain, another sign that netrin-1 ensured the integrity of the BBB.  Armed with these findings suggesting netrin-1 protects the BBB, the group tested the potential of netrin-1 in ameliorating EAE symptoms, which are similar to those of people with MS.

The data findings showed that by administering netrin-1 to mice before the EAE disease was induced the animals had less severe disease, delayed disease onset, fewer lesions in their brain, fewer markers of inflammation and better maintenance of body weight compared to mice given a sham treatment.  In mice, the team found the disease outcome is better when they’re treated with netrin-1, even when delivered after disease processes had begun.  The team state that all those observations held up in vitro as well, adding that the medical community now know that Sonic is above netrin-1 in the signaling pathway, but need to understand what else Sonic hedgehog is doing.

Moving forward, the researchers hope to further elucidate the pathway through which Shh and netrin-1 operate, with an aim toward finding more effective ways to uphold the barrier and perhaps one day treat diseases like MS.

Source:  University of Pennsylvania

Inflammation in a multiple sclerosis lesion prompts the blood-brain barrier to enhance the expression of netrin-1 (green) to limit immune-related damage. Blood-brain barrier vessels were labeled red and cell nuclei were stained blue.  Credit:  University of Pennsylvania.
Inflammation in a multiple sclerosis lesion prompts the blood-brain barrier to enhance the expression of netrin-1 (green) to limit immune-related damage. Blood-brain barrier vessels were labeled red and cell nuclei were stained blue. Credit: University of Pennsylvania.

 

 

Healthinnovations View All

Michelle Petersen is the founder of Healthinnovations, having worked in the health and science industry for over 21 years, which includes tenure within the NHS and Oxford University. Healthinnovations is a publication that has reported on, influenced, and researched current and future innovations in health for the past decade.

Michelle has been picked up as an expert writer for Informa publisher’s Clinical Trials community, as well as being listed as a blog source by the world’s leading medical journals, including the acclaimed Nature-Springer journal series.

Healthinnovations is currently indexed by the trusted Altmetric and PlumX metrics systems, respectively, as a blog source for published research globally. Healthinnovations is also featured in the world-renowned BioPortfolio, BioPortfolio.com, the life science, pharmaceutical and healthcare portal.

Most recently the Texas A&M University covered The Top 10 Healthinnovations series on their site with distinguished Professor Stephen Maren calling the inclusion of himself and his team on the list a reflection of “the hard work and dedication of my students and trainees”.

Michelle Petersen’s copy was used in the highly successful marketing campaign for the mega-hit film ‘Jumanji: The Next Level, starring Jack Black, Karen Gilian, Kevin Hart and Dwayne ‘The Rock’ Johnson. Michelle Petersen’s copywriting was part of the film’s coverage by the Republic TV network. Republic TV is the most-watched English language TV channel in India since its inception in 2017.

An avid campaigner in the fight against child sex abuse and trafficking, Michelle is a passionate humanist striving for a better quality of life for all humans by helping to provide traction for new technologies and techniques within healthcare.

One thought on “Researchers identify how the blood-brain barrier is maintained to control ‘tight junction’ function. Leave a comment

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.