Chenghua Gu, PhD, professor of neurobiology
Blood vessels in the body serve as a highway system for transporting oxygen, glucose, and other beneficial nutrients and molecules to different parts of the body where they promote the health of the cells, as well as for transporting harmful particles such as viruses and bacteria.
The blood vessels in the brain, however, are different from the blood vessels in other parts of the body. Brain blood vessels have a gate, known as the Blood-Brain Barrier, that gives the circulatory system of the brain more selectivity – vital nutrients such as sugar and vitamins are allowed to pass through and reach neurons, but harmful viruses and bacteria are blocked. This special selectivity of the blood-brain barrier maintains the clean environment of the brain that allows it to function properly.
While the selectivity of the blood-brain barrier is generally beneficial to the brain, it comes with a cost: the gate is so selective that it also blocks therapeutic agents that could be helpful in treating diseases of the brain. For years scientists have tried to understand how the blood-brain barrier is constructed, thinking that once this was understood, clinicians might be able to temporarily open the gate to allow the entry of medicines. My colleagues and I at Harvard Medical School recently discovered a molecule that may be responsible for the limited permeability of the blood-brain barrier. By blocking this molecule’s activity temporarily, therapeutic drugs may be able to gain access to the brain’s vascular system and to deliver treatment to neurons associated with certain neurological disorders.
When I began this study, I asked why the cells that make up the blood vessels in the brain are different compared to those making up blood vessels in the skin, liver, and other parts of the body. Why don’t the blood vessels outside the brain have such a barrier?
The walls of blood vessels are made up of specialized cells called endothelial cells that are “cemented,” or adhered, to one another. At first we thought that the cement was more porous in blood vessels of the body than in those found in the brain, and that this lack of porosity in the brain is what constituted the blood-brain barrier. However, we found that the cement was similar in all blood vessels, regardless of location.
Our study revealed that it is the porosity of the endothelial cells themselves that varies: those in blood vessels in the brain are less porous than those in blood vessels in the rest of the body. We found that MFSD2a, a protein in the endothelial cells of the mouse brain, prevents a process known as transcytosis, which allows substances to be transported through the wall of the blood vessels in small capsules called vesicles. Transcytosis occurs everywhere in the body, but in the brain’s blood vessels, it is suppressed by MFSD2a.
This work is especially exciting because MSFD2a is also found in the human brain. It is therefore possible that temporarily blocking MFSD2a activity could allow the delivery of drugs that could treat neurological diseases such as brain tumors, epilepsy, infection, psychiatric disorders, autism, Alzheimer’s disease, and Parkinson’s disease. Moreover, because blood-brain barrier degradation has been linked to diseases such as Alzheimer’s disease and multiple sclerosis, boosting MSFD2a may strengthen the barrier and alleviate the devastating effects of these neurological diseases.