Novel role of the blood-brain barrier in neuron function and damage

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Summary: Signals that come from the cells of the blood-brain barrier also play a direct role in controlling what happens to the neurons that the barrier protects.

Source: Buck Institute

While the role of the blood-brain barrier has long been appreciated for its ability to maintain precise control over the molecules that can enter the nervous system, very little is known about how the cells that form the barrier influence the function of the nervous system.

“What we currently know about the blood-brain barrier is mostly that we don’t know much beyond the basics,” says Buck Institute professor Pejmun Haghighi, Ph.D., who discovered a new role for these cells.

Haghighi is lead author of a study published in the August 19, 2022 issue of the Proceedings of the National Academy of Sciences (PNAS) which offers for the first time evidence, in fruit flies, that signals from barrier cells also play a direct role in controlling what happens in the nerve cells that the barrier protects.

Breakdown of the blood-brain barrier accompanies many neurological conditions, including epilepsy and multiple sclerosis, and neurodegenerative diseases of aging, such as Alzheimer’s disease and Parkinson’s disease.

“We find that the barrier is not only a protective control but also a source of regulation,” says Haghighi. “It can cause problems rather than just being a byproduct of neurodegeneration. We are now learning that there is definitely a two-way street.

The discovery introduces a new conceptual approach to searching for therapies that could reverse the damage caused by neurodegenerative diseases and designing strategies to move drugs past the blood-brain barrier to target sites in the brain.

Haghighi explains his team’s findings in these terms: imagine there is a doorman at a door who checks identification and makes sure that anyone entering is supposed to be there, and also checks the identity of those who entered through a back door and kicks out anyone not supposed to be there. This is the job of the blood-brain barrier.

Now imagine that in addition to being a simple security check, the guard also gives instructions on where to go and what to do. The second feature is what Haghighi’s team revealed.

The team used fruit fly larvae for their study. While fruit flies lack the complexity of vertebrate blood-brain barriers, many properties are the same, in a system that is much easier to study.

The key cells that form a barrier for neurons in fruit flies are specialized glia that function similarly to the specialized endothelial cells that form the essential part of the blood-brain barrier in higher vertebrates, including humans.

The investigation began by focusing on enzymes called metalloproteinases because of their critical potential in interactions between glia and neurons.

Breakdown of the blood-brain barrier accompanies many neurological conditions, including epilepsy and multiple sclerosis, and neurodegenerative diseases of aging, such as Alzheimer’s disease and Parkinson’s disease. Image is in public domain

Using a genetic approach to research what regulates the expression of these enzymes, the team identified a pathway known as Notch signaling. Notch is found in both fruit flies and humans. It is associated with human diseases of the vascular system, dementia and strokes.

“We didn’t intend to study Notch, but we found that it was the main player in maintaining the blood-brain barrier,” says Haghighi.

They found that Notch signaling in glia regulates the overall structure of the barrier. When the signal is blocked, not only is barrier function impaired, but the “fundamental work of the nervous system is affected,” he says, including the release of neurotransmitters and muscle contractions.

Under certain conditions, manipulation of Notch signaling affected how neurons fired, even though the blood-brain barrier remained intact. This indicates that there is signaling in the blood-brain barrier that goes beyond simply maintaining barrier function, says Haghighi.

The degradation of the barrier function may be the cause of a dysfunction of the nervous system, rather than being correlated to it or even being the consequence of other damage.

“Because we are seeing disruption of barrier function, without any obvious barrier leakage, having an effect on synaptic function, this is a conceptual breakthrough,” he said, because no one had observed cells of the barrier itself controlling the activity of neurons before.

“We cannot yet say what is the cause and what is the effect, but we can say that it is beyond a simple correlation that some patients have a rupture of the blood-brain barrier: it is a significant defect associated with neurodegeneration,” Haghighi said.

Their findings open up a completely different perspective for the development of novel therapies aimed at counteracting the barrier function damage associated with neurodegenerative diseases.

To build on this intriguing premise, Haghighi’s team is pursuing a number of directions. They looked at two of the main genetic mutations in Alzheimer’s disease and found that a very rapid breakdown of the blood-brain barrier occurs when these genes are expressed in flies.

The team’s bioinformatics studies suggest that nearly all of the genes identified in flies have counterparts in humans, and that the functions of many of these human genes are unknown.

Not much is yet known about human versions of Notch and metalloproteinases, beyond the fact that a mutation in a human Notch protein leads to breakdown of the blood-brain barrier and dementia and that several human metalloproteinases are found to be abnormally expressed in neurodegenerative diseases and blood-brain barrier defects.

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“We hope that we can work backwards to comprehensively understand what the relationship between the blood-brain barrier and neurodegenerative diseases is,” says Haghighi.

“We are exploring all of these signaling pathways to see if we can translate our findings of larval synaptic function into a more universal model of age-dependent neurodegeneration.”

About this neuroscience research news

Author: Press office
Source: Buck Institute
Contact: Press Office – Buck Institute
Image: Image is in public domain

Original research: Free access.
“Delta/Notch signaling in glia maintains motor nerve barrier function and synaptic transmission by controlling matrix metalloproteinase expression” by Pejmun Haghighi et al. PNAS


Summary

Delta/Notch signaling in glia maintains motor nerve barrier function and synaptic transmission by controlling matrix metalloproteinase expression

Although the role of barrier function in establishing a protective, nutrient-rich, and ionically balanced environment for neurons has been appreciated for some time, little is known about how signaling signals from cells barrier-forming molecules help maintain barrier function and influence synaptic activity. .

We have identified Delta/Notch signaling in subperineural glia (SPG), a glial type crucial for Drosophila motor axon sheathing and the blood-brain barrier, essential for controlling the expression of matrix metalloproteinase 1 (Mmp1), a major regulator of the extracellular matrix (ECM).

Our genetic analysis indicates that Delta/Notch signaling in SPG exerts an inhibitory control over Mmp1 expression. In the absence of this inhibition, the abnormally increased activity of Mmp1 disrupts septate junctions and the glial envelope of peripheral motor nerves, compromising the release of neurotransmitters at the neuromuscular junction (NMJ).

Time-controlled, cell-type-specific transgene analysis shows that Delta/Notch signaling inhibits Mmp1 transcription by inhibiting c-Jun N-terminal kinase (JNK) signaling in SPG.

Our results provide mechanistic insight into the regulation of neuronal health and function via glial cell-initiated signaling and open a framework for understanding the complex relationship between ECM regulation and maintenance of barrier function.

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