8/18/2023 0 Comments Blood brain barrier function![]() The team's bioinformatics studies suggest that almost all of the identified genes in flies have homologs in humans and that the functions of many of these human genes are unknown. They have been looking at two of the primary gene mutations in Alzheimer's disease and have found a very rapid breakdown of the blood-brain barrier occurs when these genes are expressed in flies. To build on this intriguing premise, Haghighi's team is pursuing a number of directions. Their findings open up a completely different perspective for developing novel therapeutics aimed at countering damage in barrier function related to neurodegenerative diseases. "We can't say what is cause and what is effect yet, but we can say that it is beyond just a correlation that some patients have breakdown of blood-brain barrier: it is an important defect associated with neurodegeneration," Haghighi said. "Because we are seeing disruption in barrier function, without any obvious leakiness of the barrier, having an effect on synaptic function, this is a conceptual advance," he said, as no one had observed cells from the barrier itself controlling neuron activity before. Breakdown in barrier function may be causing nervous system dysfunction, rather than being correlated with it or even a consequence of other damage. That indicated that there is signaling happening in the blood-brain barrier that is beyond just the maintenance of the barrier function, says Haghighi. Under certain conditions, manipulation of Notch signaling affected how neurons fired, even though the blood-brain barrier remained intact. When the signal is blocked, not only is barrier function impaired, but the "fundamental work of the nervous system is affected," he says, including neurotransmitter release and muscle contractions. They discovered that Notch signaling in glia regulates the overall structure of the barrier. "We weren't planning on studying Notch, but we found it was the main player in the maintenance of the blood-brain barrier," says Haghighi. It is associated with human diseases of the vasculature, dementia and stroke. Notch is found in both fruit flies and humans. Using a genetic approach to look for what regulated expression of these enzymes, the team identified a pathway that is known as Notch signaling. ![]() The investigation began with a focus on enzymes called metalloproteinases because of their potential to be critical in interactions between glia and neurons. The key cells that provide a barrier for neurons in fruit flies are a specialized glia that function similarly to specialized endothelial cells that form the critical part of the blood brain barrier in higher vertebrates including humans. While fruit flies do not have the complexity of vertebrate blood-brain barriers, many of the properties are the same, in a system much easier to study. The team used fruit fly larvae for their study. The second function is what Haghighi's team revealed. Now imagine that beyond just being a security check, the gatekeeper also gives out directions about where to go and what to do. ![]() That is the job of the blood-brain barrier. Haghighi explains his team's findings as such: Imagine that there is a gatekeeper at a door that checks IDs and ensures that anyone entering is supposed to be there, and also checks the ID of those who entered through a back door and kicks out anyone not supposed to be there. The finding introduces a new conceptual approach to looking for therapies that could counter damage caused by neurodegenerative diseases, and devising strategies to get drugs past the blood-brain barrier to target sites in the brain. We are learning now that there is definitely a two-way street." "It can cause problems rather than simply being a byproduct of neurodegeneration. "We are finding that the barrier is not just a protective check but also a source of regulation," Haghighi says. The 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. Haghighi is the senior author of a study publishing in the Augissue of the Proceedings of the National Academy of Sciences (PNAS) that offers for the first time evidence, in fruit flies, that signals originating in the cells of the barrier also play a direct role in controlling what happens in the nerve cells the barrier is protecting.
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