A new role for the blood-brain barrier in neuronal function and damage

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

A source: Garden Institute

Although the role of the blood-brain barrier has long been appreciated for its ability to precisely control what molecules can enter the nervous system, little is known about how the cells that make up the barrier affect the functioning of the nervous system.

“What we know now about the blood-brain barrier, we don’t really know much more than the basics,” says Dr. Pejmun Haghighi, a professor at the Garden Institute who discovered a new role for these cells.

Hagighi is the senior author of the study, published on August 19, 2022. Proceedings of the National Academy of Sciences (PNAS) This is the first evidence in fruit flies that signals from barrier cells also play a direct role in controlling what happens in nerve cells that protect the barrier.

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

“We’re finding that the fence is not just a protective check, but also a source of regulation,” says Haghighi. “It’s not just a byproduct of neurodegeneration, it can cause problems. We are now learning that there is a two-way street.”

The research introduces a new conceptual approach to the search for therapies that can counteract the damage caused by neurodegenerative diseases and develops strategies to deliver drugs across the blood-brain barrier to target sites in the brain.

Hagighi explains his team’s findings this way: Imagine having a doorman at the door who checks someone’s ID and ensures that those who come in are supposed to be there, and also checks the IDs of those who come in through the back door and turns anyone away. I am there. This is the work of the blood-brain barrier.

Now imagine a gatekeeper giving instructions on where to go and what to do in addition to security checks. The second feature is what Hagighi’s team discovered.

The team used fruit fly larvae for their study. Although lacking the complexity of the vertebrate blood-brain barrier of fruit flies, many of the properties are the same, making the system much easier to study.

The primary cells that inhibit higher neurons in fruit flies are specialized glia that function similarly to the specialized endothelial cells that form an important part of the blood brain barrier in vertebrates, including humans.

The research began by focusing on enzymes called metalloproteinases, because they are important in the interaction between glia and neurons.

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

Using a genetic approach to look for how the expression of these enzymes is regulated, the team identified a pathway known as Notch signaling. Notch is found in both fruit flies and humans. It is associated with human vascular disease, dementia and stroke.

“We didn’t plan to study Notch, but we found it to be a key 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 disrupted, but “basic nervous system function is affected,” he says, including neurotransmitter release and muscle contraction.

Under certain conditions, manipulation of Notch signaling affected neuronal firing despite intact blood-brain barrier. This suggests that there is a signal at the blood-brain barrier that is not limited to maintaining barrier function, says Haghighi.

Impairment of barrier function can lead to dysfunction of the nervous system, rather, as a result of contact with it or other damage.

“Because we’re seeing barrier dysfunction that affects synaptic function without obvious barrier leakage, that’s a conceptual breakthrough,” he said, because no one had previously observed cells controlling neuronal activity at the barrier. .

“We can’t yet say what is cause and what is effect, but we can say that in some patients, blood-brain barrier disruption is more than just a correlation: it is an important defect associated with neurodegeneration,” Haghighi said. .

Their findings open up a completely different perspective for the development of new therapies targeting damage in barrier function associated with neurodegenerative diseases.

To build on this intriguing premise, Hagighi’s team is pursuing a number of directions. They looked at two key Alzheimer’s disease gene mutations and found that the blood-brain barrier breaks down very quickly when these genes are expressed in flies.

The team’s bioinformatics research shows that almost all of the genes identified in flies have homologues in humans, and the functions of many of these human genes are unknown.

Not much is known about the human versions of Notch and metalloproteinases, except that mutations in the human Notch protein cause blood-brain barrier damage and dementia, and several human metalloproteinases have been found to be abnormally expressed in neurodegenerative diseases. diseases and blood-brain barriers.

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It shows the brain

“We hope to be able to work backwards to understand the relationship between the blood-brain barrier and neurodegenerative diseases,” says Haghighi.

“We are investigating all of these signaling pathways to see if our findings can be translated from larval synaptic function to a universal age-dependent model of neurodegeneration.”

Neuroscience research news about it

Author: Press service
A source: Garden Institute
The connection: Press service – Garden Institute
Photo: Image is in the public domain

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


Abstract

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

Although the role of barrier function in creating a protective, nutrient-rich, and ionically balanced environment for neurons has been appreciated for some time, little is known about how signaling from barrier cells affects barrier function maintenance and synaptic activity. .

We identified Delta/Notch signaling in subperineural glia (SPG), an important glial type for this. Drosophila Motile axon sheathing and the blood-brain barrier are required to control the expression of matrix metalloproteinase 1 (Mmp1), a key regulator of the extracellular matrix (ECM).

Our genetic analysis suggests that Delta/Notch signaling in the SPG exerts an inhibitory control on Mmp1 expression. In the absence of this inhibition, abnormally enhanced activity of Mmp1 disrupts septal junctions and the glial covering of peripheral motor nerves, impairing neurotransmitter release at the neuromuscular junction (NMJ).

Time-controlled and cell-type-specific transgenic analysis shows that Delta/Notch signaling inhibits the transcription of Mmp1 through c-Jun N-terminal kinase (JNK) signaling in the SPG.

Our results provide mechanistic insight into the regulation of neuronal health and function by glial-initiated signaling and pave the way for understanding the complex relationship between ECM regulation and the maintenance of barrier function.

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