Many neurodegenerative disorders exist today, and several of these diseases are fatal and untreatable. The pathological mechanism for many neurodegenerative diseases has not been discovered yet, however most of these diseases systematically infect certain cranial tissues. One such tissue is a semi-permeable membrane that surrounds the brain and spinal cord. This membrane is known as the blood brain barrier (BBB), and understanding the structure of this barrier is vital to treating diseases that involve it.
Keywords: Blood-Brain barrier, lymphatic system, neurodegenerative diseases
The brain and spinal cord are two of the most vital organs in the nervous system.
These two components are unique in that they are separated from circulating blood by a tissue “barrier” that acts like a semi-permeable membrane. The idea of a “barrier” separating these two parts of the body was first hypothesized by the bacteriologist, Paul Ehrlich (Palmer, 2010). Ehrlich created his hypothesis by injecting dyes intravenously to test what intracranial tissues were affected and stained as a result.
He found that only the surrounding organs and tissues were affected and in conclusion hypothesized that the CNS had a much lower affinity for the dyes than did the other tissues. His hypothesis however did not last long, and with continuing research, was soon negated by one of his students Edwin Goldmann (Palmer, 2010). As the testing continued, Goldmann revealed that the injection site was key. When injected directly into the spinal cord, his results showed that surrounding organs were untouched and only the brain and spinal cord were stained (Palmer, 2010).
This discovery lead to a growth of understanding and mapping of the blood brain barrier and its function.
The blood brain barrier is composed of a single layer of blood vessel endothelial cells that are accompanied by the coupling of astrocytes, pericytes and macrophages on their outer surface. These endothelial cells are found throughout the entirety of blood vessels among the CNS and have several distinguishing characteristics. Compared to the other endothelial cells outside of the CNS, the ones within the BBB are characterized by their meticulously tight junctions and their absence of fenestrations (Ballabh, et. al., 2003). These two elements define the characteristic “blocking” of exogenous substances. In the article “The role of the blood – CNS barrier in CNS disorders and their treatment” Alan M. Palmer explains that due to the great distance between capillaries within the cerebrovascular system, solute equilibration of the brain’s interstitial space is maintained by small molecules with the ability to permeate this barrier. With this knowledge we are able to identify the BBB as a highly selective semipermeable membrane, meaning, this barrier regulates what ions, molecules, and other cells are allowed to pass between the blood and brain. These attributes allow the BBB to act as a natural defense to protect the body against toxic and infectious agents, which in turn, aids in maintaining the perfect solute concentration needed for the CNS to function properly (Palmer, 2010). As stated by Palmer, the BBB also functions to minimize damage to the CNS done by the immune system as well as plays a key part in the detoxification process of several different transporters.
The exact mechanism of action for many neurological diseases such as Alzheimer’s and Creutzfeldt-Jakob Disease, among many others, is unknown. This is in large part due to the lack of knowledge over the structure of the BBB and mechanisms of the “glymphatic system”. The glymphatic system is a portmanteau of the glial and lymphatic systems, and “cleans” the brain by removing tainted CSF containing toxins such as misfolded proteins and cellular wastes.
Alzheimer’s Disease is a neurodegenerative disorder characterized by the buildup of plaques that form from the accumulation of beta-amyloid monomers produced in the brain (Peng et al., 215-217). A theory as to how these beta-amyloid plaques form is through ineffective fluid flow during the “cleaning” process of the glymphatic system (Peng et al., 217) . The glymphatic system cleans the brain by increasing the amount of cerebrospinal fluid (CSF) that flows through the brain. During this increased flow, concentration-mediated diffusion causes the mass transfer of waste and toxin solutes from the brain’s interstitial spaces into the CSF. Returning to the beta-amyloid structures, researchers have shown that in mice a dysfunctional glymphatic system results in much higher rates of beta-amyloid accumulation, which is strongly correlated to the emergence of Alzheimer’s (Peng et al., 220-225). While mapping the glymphatic system may not provide a treatment pathway directly, this study’s results indicate that the buildup of beta-amyloid monomers and polymers would be a good early warning mechanism for people at risk of developing Alzheimer’s.
Creutzfeldt-Jakob Disease (CJD) is another neurodegenerative disorder in which the cells in the brain produce misfolded proteins, and the accumulation of these proteins inhibits normal neuron and signaling functions (Sattar 189). These misfolded proteins are due to prions, which are misfolded prions themselves. The prions are initially monomers after being introduced to the body, and by an unknown process form long polymeric strands. Later, some monomers break off the first strand and begin forming a new strand (Clarke, Jackson and Collinge 185-195). The number and length of these strands increases exponentially with time, and there is no known way to halt the progression of the disease. Fortunately, the number of prions initially present after introduction to the body drastically increases the duration of the incubation period before symptoms manifest (Masel, Jansen and Nowak 139-152). Theoretically it could be possible to devise a drug that can bypass the BBB and specifically target prions. The drug doesn’t have to eliminate all the prions, it just needs to decrease the number of monomers early on. If the initial number of prions is reduced enough, a person might be able to go their entire lives without the symptoms of CJD negatively impacting their life.
Many untreatable neurodegenerative disorders involve the blood brain barrier, and difficulties in researching this type of tissue greatly hinder research efforts into neurodegenerative pathology. The first step in understanding a part of the body is to learn its structure and function. The function of the blood brain barrier is known however its detailed structure remains unclear. Part of the reason the BBB is so hard to map is that its capillary vessels run parallel to many circulatory vessels, and it is difficult to distinguish between the two. A recent breakthrough in mapping the BBB and its vessels occurred in 2017 when researchers proved that meningeal lymphatic structures in the brain can be selectively highlighted for magnetic resonance imaging (MRI) (Absinta et al., 2017). The study found that Gadobutrol, a gadolinium (III) chelate used as an MRI contrast chemical, showed selective permeability for lymphatic tissue in the brain. The researchers described Gadobutrol as having a “high propensity to extravasate across a permeable capillary endothelial barrier” (Absinta et al., 2017). This means that the contrasting agent has a strong tendency to diffuse into cranial lymphatic capillary tissue instead of circulatory tissues that carry blood. Results of the study produced high resolution images of the lymphatic capillaries found in the outer layer of the meninges, paving the way for further lymphatic capillary mapping studies (Absinta et al., 2017).