Recent Research Uncovers Mystery of the Blood-Brain Barrier

by Klaus Müller
5 comments
Blood-Brain Barrier Substrates

In a microscopic image, astrocytes are depicted in green, while immune cells are marked in red. The basement membranes of the blood vessels appear in white. Image Credit: University of Münster / University Hospital Bonn (UKB)

Researchers have successfully pinpointed new substrates of gelatinase that play a pivotal role in the functioning of the astroglial barrier.

During episodes of neuroinflammation, immune cells such as leukocytes breach the formidable blood-brain barrier, with matrix metalloproteinase (MMP)-2 and -9, known as gelatinases, serving as critical factors in this process. Until recently, the precise substrates targeted by these enzymes during this phenomenon remained unidentified. Employing an exceptionally sensitive mass spectrometry-based secretome technique, a team of scientists hailing from the University of Münster and Bonn University Hospital has now managed to identify numerous molecules cleaved from the cell surfaces of astrocytes.

In this pursuit, they have curated a distinctive database housing the MMP-2/-9 substrates specifically related to the establishment and preservation of the barrier, as well as the intercommunication between astrocytes and neurons. These groundbreaking findings have been recently published in the esteemed journal Science Advances.

The endothelial cells lining the inner walls of cerebral blood vessels form a protective barricade shielding the brain through closely connected junctions. However, the formation of a fully functional blood-brain barrier (BBB) necessitates the presence of underlying astrocytes, a type of glial cell. During neuroinflammation, the endothelial and astroglial layers emerge as two distinct molecular and functional barriers guarding against the intrusion of white blood cells, known as leukocytes.

Nevertheless, investigations into multiple sclerosis (MS) have unveiled that disease symptoms do not manifest until immune cells penetrate the astroglial layer.

“This underscores their crucial role in upholding the functional integrity of the BBB and their autonomy from the endothelial barrier,” asserts Prof. Lydia Sorokin, director of the Institute of Physiological Chemistry and Pathobiochemistry at the University of Münster. “However, in contrast to leukocyte penetration of the endothelial barrier, our understanding of subsequent processes at the astroglial layer has remained limited.”

Information regarding processes occurring on the cell surfaces of astrocytes has been scarce.

It is well-established that gelatinases, matrix metalloproteinase (MMP)-2 and -9, regulate the infiltration of leukocytes into the brain during neuroinflammation. The activity of these two protein-cleaving enzymes serves as an early indicator of immune cell invasion into the brain parenchyma and, to date, represents the sole specific marker of ongoing neuroinflammation.

“Evidence suggests that MMP-2 and MMP-9 exert both positive and negative effects on the BBB. Therefore, unraveling their substrate specificity at the brain parenchymal boundary will enhance our comprehension of the molecular processes essential for astroglial barrier function,” remarks Prof. Sorokin.

The Secretome: Unlocking Peptides from Proteolytic Cleavage

Identifying the precise locations of enzyme cleavage presents a formidable challenge. The research team capitalizes on recent advancements, particularly in mass spectrometry (MS), to scrutinize the secretome, a technique capable of comprehensively detecting proteins secreted by cells. In this study, they have further refined this approach to identify proteolytic cleavages of cell membrane-associated proteins. “Our methodology detects protein fragments released into the extracellular space without the need for biochemical enrichment, rendering it highly sensitive,” explains Prof. Felix Meissner, director of the UKB’s Institute of Innate Immunity. Employing a tailored secretome MS technique, the team has identified two principal categories of compounds liberated by MMP-2/MMP-9 from the surface of astrocytes. Validation of these novel substrates associated with neuroinflammation was carried out in a mouse model of multiple sclerosis and human MS samples.

Collectively, the integration of the secretome MS technique with insights into the astroglial barrier has yielded an exclusive repository of previously undisclosed gelatinase substrates, likely contributing to the functionality of the astroglial boundary. Moreover, evidence suggests that MMP-2/MMP-9 activity may also influence the communication between astrocytes and neurons.

“Our methodology for identifying proteolytic processes that govern astroglial barrier function is proving effective and offers promising avenues for future research aimed at comprehending the molecular intricacies of the astroglial barrier and its role in bolstering the BBB,” concludes Prof. Meissner.

Reference: “Secretomics reveals gelatinase substrates at the blood-brain barrier that are implicated in astroglial barrier function” by Miriam Burmeister, Annika Fraunenstein, Martin Kahms, Laura Arends, Hanna Gerwien, Tushar Deshpande, Tanja Kuhlmann, Catharina C. Gross, Venu N. Naik, Heinz Wiendl, Juergen Klingauf, Felix Meissner, and Lydia Sorokin, published on July 19, 2023, in Science Advances.
DOI: 10.1126/sciadv.adg0686

Frequently Asked Questions (FAQs) about Blood-Brain Barrier Substrates

What is the significance of this research?

This research is significant because it identifies previously unknown gelatinase substrates related to the astroglial barrier, shedding light on their role in neuroinflammation and the blood-brain barrier.

Why are gelatinase substrates important?

Gelatinase substrates are important because they play a crucial role in regulating the invasion of immune cells into the brain during neuroinflammation, making them a key marker for this process.

How was the research conducted?

The research utilized a sensitive mass spectrometry-based secretome method to identify these substrates. This approach allowed for the comprehensive detection of proteins secreted by cells and the identification of proteolytic cleavages of cell membrane-associated proteins.

What implications does this research have for diseases like multiple sclerosis (MS)?

The research has implications for diseases like MS because it reveals that disease symptoms in MS do not manifest until immune cells penetrate the astroglial layer, highlighting the importance of understanding the processes at this layer.

How might this research contribute to future studies?

This research provides a unique database of gelatinase substrates and offers opportunities for future research to delve deeper into the molecular intricacies of the astroglial barrier and its role in maintaining the blood-brain barrier.

More about Blood-Brain Barrier Substrates

  • Science Advances Article: The full research article titled “Secretomics reveals gelatinase substrates at the blood-brain barrier that are implicated in astroglial barrier function” published in Science Advances.

  • University of Münster: The official website of the University of Münster, where some of the research was conducted.

  • University Hospital Bonn (UKB): The official website of the University Hospital Bonn (UKB), where part of the research took place.

  • Matrix Metalloproteinase (MMP)-2 and -9: Information on matrix metalloproteinase (MMP)-2 and -9 and their role in neuroinflammation.

  • Blood-Brain Barrier: Information on the blood-brain barrier and its importance in protecting the brain.

  • Multiple Sclerosis (MS): Information about multiple sclerosis (MS) and its impact on the central nervous system.

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5 comments

GrammarNazi October 3, 2023 - 2:57 am

Good read, but watch out for them typos and missing punctuation.

Reply
SeriousReader October 3, 2023 - 3:37 am

Interesting research, but need more details for full understanding. How it help treat diseases?

Reply
ResearchGeek October 3, 2023 - 4:29 am

MS implications are huge! More studies needed, can’t wait for updates.

Reply
SciEnthusiast October 3, 2023 - 7:47 am

So, they’re using mass spec to find proteins? Great stuff, but they could explain it simpler.

Reply
Reader123 October 3, 2023 - 2:21 pm

omg this is some crazy sci stuff, like gel thingies in the brain? cool!

Reply

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