Dysfunction in the Blood-Brain Barrier May Harm Neural Function Even Prior to Leakage
Researchers here present evidence for the proposition that the blood-brain barrier doesn't just become leaky with age, but also causes disruption of neural function in other ways yet to be fully explored. The primary function of the blood-brain barrier is to regulate passage of molecules and cells into the central nervous system, and when that breaks down the consequence is chronic inflammation in brain tissue, contributing to the onset and progression of neurodegenerative conditions. It seems that the harms may start somewhat before the blood-brain barrier is sufficiently compromised to leak, however.
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. "We are finding that the barrier is not just a protective check but also a source of regulation. It can cause problems rather than simply being a byproduct of neurodegeneration. We are learning now that there is definitely a two-way street."
The team used fruit fly larvae for their study. 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 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.
The investigation began with a focus on enzymes called metalloproteinases because of their potential to be critical in interactions between glia and neurons. Using a genetic approach to look for what regulated expression of these enzymes, the team identified a pathway that is known as Notch signaling. Notch is found in both fruit flies and humans. It is associated with human diseases of the vasculature, dementia, and stroke. They discovered that Notch signaling in glia regulates the overall structure of the blood-brain barrier. When the signal is blocked, not only is barrier function impaired, but the fundamental work of the nervous system is affected, including neurotransmitter release and muscle contractions.
Under certain conditions, manipulation of Notch signaling affected how neurons fired, even though the blood-brain barrier remained intact. That indicated that there is signaling happening in the blood-brain barrier that is beyond just the maintenance of the barrier function. Breakdown in barrier function may be causing nervous system dysfunction, rather than being correlated with it or even a consequence of other damage.