As one of the most complex and delicate organs of the human body, the brain constitutes of multiple specialized parts that sustain its functions. Some of its constituent parts are responsible for facilitating its central functions such as memory and speech while others exist solely as supporting elements to the continuous function of the brain. An example of such supporting elements is the Blood-Brain Barrier (BBB). The BBB represents a protective barrier between the brain’s blood vessels and cellular components that make up brain tissue. While the role of elements like meninges, skull, and cerebrospinal fluid is to protect the brain against physical damage, the BBB’s major function is to defend the brain against disease-causing pathogens and toxins that may exist in the blood. The Blood Brain Barrier, thus, is a semipermeable boundary that restricts communication and transport of solutes between the circulatory system and the extracellular fluid of the Central Nervous system (CNS).
The BBB was first discovered in the 19th century by German scientist Paul Ehrlich. Ehrlich had injected an aniline dye intravenously into a rat when he noted that it changed the color of all body organs but not the brain. His findings were further confirmed by Goldmann and Bouffard who also ascertained that an intravenously injected trypan blue dye did not end up in the brain of rats. These early experiments suggested the permeability properties of non-neural vessels were different from those of cerebral vessels. Consequently, the findings led to the conclusion that there was a barrier between the blood and the brain. Although the term “Blood-brain-barrier” initially referred to the restriction of certain molecules into the brain, it was later adjusted to include a range of mechanisms that sustain cerebral homeostasis.
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It was not until the introduction of electron microscopes in the 1960s that scientists were able to study the structure of the cerebral endothelium and uncover the mysteries of the BBB. Today, it is widely recognized that the aspect of the BBB that provides a boundary between the brain and the blood is the ‘endothelial tight junction.’ This component consists of endothelial cells that create a lining in the interior of blood vessels. Endothelial cells are closely packed together in the capillaries within the Blood Brain Barrier to form tight junctions (Daneman 649). The tight gaps allow some elements to pass through while restricting others. For instance they allows fat-soluble molecules and some gases to pass freely and restricts potentially toxic compound molecules.
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Apart from the endothelial cells, the BBB also consists other components which are not strictly involved in restricting the passage of elements but which are involved in fashioning the selectiveness of the BBB in its function. They include pericytes, astrocytes, and the basal lamina. The cerebral capillary wall also contains a thick basement membrane which separates and encloses pericytes. This review discusses the structural and functional features of the BBB. It begins by examining the main cellular components and proceeds to explore the roles of junctions and transporters before delving into how Blood Brain Barrier functions can be inhibited by neurological disorders.
Blood Brain Barrier Components
As a compound structure, the BBB is primarily composed of four cell types namely, endothelial cells, Pericytes, astrocytes, and Microglia. Endothelial cells are lodged in a lining in the interior of the capillaries. They are closely packed together in a network that forms a barrier. The tiny spaces between them form the tight cellular junctions which are critical to the micro-vessels of the brain. Their main task is to maintain the permeability and integrity of the vessel, hence, regulating what passes through the BBB. Pericytes are deeply entrenched into the basement membrane and are closely linked to endothelial cells. There is a common consensus that pericytes are formed from the same foundation as smooth muscles cells (Zhao, Zhen, et al. 1068).
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Albeit pericytes provide structural support to micro-vessels, they also influence growth and permeability by signaling with the endothelial cells. They may also play part in immune functions such as detecting, consuming, and destroying potentially disastrous micro-organisms derived from the blood. Astrocytes, which assume star-like shapes, support the structural integrity of the BBB. They are purposely known for the role in recruiting peripheral cells, including white blood cells, into the CNS via the BBB. The final types of cells, the microglia are located just beyond the BBB. They are not intrinsically considered to be an integral part of the BBB, but are important in providing immunity. The function of these cells is to survey the CNS for microbes in order to engulf and damage them. Hence, microglia act as another line of defense against toxins and pathogens that cross the BBB. The next sections will expound on each of these cells in detail.
The body contains many types of endothelial cells. Generally, endothelial cells form a layer that regulates the exchange of substances between surrounding tissues and the bloodstream. Endothelial cells in the BBB are quite different from other endothelial cells in that they achieve a more restrictive permeability to protect the brain (Daneman 649). To attain a high restrictive permeability, endothelial cells in the BBB possess certain characteristics. First, they contain a smaller number of endocytic vesicles to impede transcellular flux. Second, they have no fenestrations. Third, they possess a high electrical resistance. This characteristics materializes due to the tight junctions which inhibit Para cellular flux. Fourth, they have a high volume of mitochondria. This reflects a higher rate of metabolism. Fifth, endothelial cells of the BBB contain specialized transport systems.
In terms of function, microvascular endothelial cells of the BBB regulate the transport of micronutrients and macronutrients besides managing receptor-mediated signaling, osmoregulation, and trafficking of leukocytes. The structural components that facilitate these functions are (1) tight junctions, which are composed of proteins such as claudins, occludin, and occludens, and cingulin; (2) adherent junctions, which are composed of catenins, cadherins, actinin, and cinculin; and (3) junctional adhesion molecules. The cytoplasm of endothelial cells has a standard thickness, limited pinocytotic vesicles, and lacks fenestrations. The cytoplasm represents the hollowed-out section of the cell membrane that contains fluid and which allows the transport of nutrients.
Endothelial cells are bordered by the basal lamina, which is essentially generated by pericytes, a matrix that exists outside the cell and which contains glycoproteins, collagens, proteoglycans, and laminins, among other proteins. Modification of the basal membrane can significantly affect the microvasculature permeability of the brain and this is especially evident in the occurrence of stroke and inflammation both of which lead to edema. The endothelial cells of the BBB are genetically or environmentally based. Some scholars maintain that endothelial cells of the BBB are genetically predisposed to becoming brain endothelial cells. It is also possible that they become brain endothelial cells due to being subjected to the brain microenvironment. Various experiments have provided substantiation to the later hypothesis. Such studies show that the local microenvironment of the brain is responsible for causing the unique differentiation of BBB endothelial cells. Factors of the microenvironment that may lead to the unique BBB functions of brain endothelial cells comprise neighboring cells, flow, and the extracellular matrix.
Pericytes are located embedded in the vascular basement membrane on the abluminal surface of endothelial cells (Zhao, Zhen, et al. 1068). They are physically connected to the endothelial cells through gap junctions as well as through peg and socket mechanisms. Their primary role is to give stability to the endothelial cell monolayer. Pericytes achieve their structural support role through the regulation of angiogenenesis and creation of extracellular matrix. Pericytes are particularly important in the growth of tight junctions and restrictive functions of the BBB. Additionally, there is unwanted transfer of signals between endothelial cells and pericytes. Similar to endothelial cells, there is a distinct divergence between pericytes if the CNS and pericytes of the periphery. Pericytes located in the CNS are larger in number compared to those in the periphery. Hence, the ratio of endothelial cells to pericytes is much greater.
Apart from providing structural support to the endothelial layer, pericytes can regulate blood flow in accordance with neural activity. This suggests their important part in the mediation of vascular tone and neural communication that regulates that role. Pericytes communicate with neurons, endothelial cells, and astrocytes to regulate the structure and function of the BBB. As indicated above, pericytes can initiate communication with secretory aspects over and above alterations in water channels and fluid movement. Therefore, interruptions in one cell type can affect other cell types. For instance, pericytes can be lost due to peripheral insulins resistance and have been shown to degenerate because of Alzheimer’s disease (Zlokovic, Berislav V. 188). The loss of pericytes has also been shown to be the cause of BBB breakdown and eventual dysfunction of BBB functions. The loss of pericytes primarily accelerates the advancement of the pathology of Alzheimer’s disease, including tau pathology, neuronal loss, and amyloid beta (Aβ) deposition. The next type describes the role of astrocytes and how they contribute to the function of the BBB.
Astrocytes are the most copious cells in the brain. They consist of star-shaped elements that form an environment in which all aspects of neuronal functions, including survival, metabolism, development, and neurotransmission, occur (Daneman 651). In essence, they are elements of the neuroglia, which literally means nerve cement or glue. The neuroglia is the tissue that support the CNS. The primary role of astrocytes it to regulate the local environment. They function as metabolic sensors that help in the repair and maintenance support via the release of facilitator molecules. The astrocytic end feet enclose the vascular tube, helping in the regulation of water and ion. The astroglial water channels that controls solute movement and perivasculat fluid transfer across the glyphatic system is the Aquaporin-4. The glymphatic system is a distinct mechanism of exchange between the interstitial fluid of the CNS and the perivascular cerebrospinal fluid (CSF). Through this system, the brain is able to control fluid flow throughout the CNS and facilitate elimination of toxins. Furthermore, the linkage between blood vessels and neurons helps astrocytes to send and receive signals about the flow of blood and control water content within the brain. There are 11 distinct phenotypes of astrocytes. Among these, eight are enmeshed in blood vessel interactions.
A symbiotic relationship exists between astrocytes and endothelial cells. Astrocytes discharge various chemical factors such as growth factors that stimulate aspects of the BBB phenotype. A lattice of fine lamellae is formed by the end feet of the glial cells. This lattice is closely placed on the outer endothelium surface to separate capillaries from neurons. Moreover, the lattice of the fine lamellae serves as a scaffold for guiding neurons in their proper placement in the growth and direction of BBB vessels. Astrocytic glia is especially vital in the maintenance and induction of BBB phenotypes. Its role in intercellular signaling and endothelial interaction is necessary for optimal functioning of the BBB. There is mounting evidence to prove that endothelial cells impose a mutual inductive effect on astrocytes. Another role of the astrocytes is the dynamic regulation of microcirculation in the brain. The intercellular calcium responses of the astrocyte network can shape dilation of arterioles as a function of neuronal activity. Signaling between astrocytes and neurons is important in the control of energy supply to bolster neuronal functions.
The basal lamina consists of the membrane in which pericytes are embedded. It is located between astrocytes and endothelium and is made up of laminin, proteoglycans, collagens, and fibronectin, among other extracellular matrix proteins. The major role of the basal lamina is to provide structural support for the attachment of cells (Daneman 651). Cells are attached to the basal lamina through integrins which consist of transmembrane receptor proteins. The basal lamina also acts as a sheath that blocks the penetration of macromolecules. The basal lamina also houses cellular projections originating from pericytes towards the abluminal membrane in the endothelium at defined intervals. These cellular projections cover about 30 percent of the microvascular perimeter. Scholarly evidence points to the ability of pericytes to induce the tightness of BBB through regulation of proliferation of endothelial cells and the differentiation and creation of the endothelial tight junctions. Pericytes also embody a phagocytic capability which may serve certain roles in neuroimmune functions. Furthermore, pericytes are involved in the expression of receptors for given vasoactive agents such as catecholamines, endothelin I, angiotensin II, and vasopressin. This indicates that they may play a variety of roles in cerebral autoregulation.
The basement membrane is a special type of extracellular matrix that exists underneath epithelial and endothelial cells (Zhao, Zhen, et al. 1066). It has many functions which include cell anchoring, structural support, and transduction signaling. Two types of basement membrane exist in the BBB. The first is an endothelial basement membrane while the second is a parenchymal basement membrane. Physiologically, these two types of basement membranes are indistinguishable. Their appearance is only set apart in areas where pericytes exist. Structurally, the basement membrane is highly organized and stretched to a thickness of 50 to 100m. In terms of biochemistry, the basement membrane consists laminin, collagen IV, perlecan, and nidogen. This set of proteins is synthesized mainly by the endothelial cells, astrocytes and pericytes.
The proteins laminin, collagen IV, perlecan, and nidogen interact with endothelial cells within the basement membrane through the integrin receptors, which make up the transmembrane heterodimers which interlinks the endothelial cell membrane factors of growth, ligands, and development receptors. Collectively, these are involved in the regulation of cell functions such as migration, survival, adhesion, differentiation, and polarity. The dysfunction of integrin can cause abnormalities in the BBB. This is evident in mice experiments where dysfunction of integrin leads to loss of claudin and undeveloped BBB. The acute lockdown of laminin condition elimination of astrocytic laminin are precursors to the destruction of the basement membrane reduced tight junction expression, loss of polarity of astrocyte end feet, and disruption of BBB. By the same token, it has been demonstrated in mice that the lack of laminin lead to disruption of the BBB due to loss of pericyte coverage and loss of tight junction and adheren junction proteins.
Immune Cells (Microglia)
Microglia are types of glial cells that exist in the CNS. They consist of 10 to 15 percent of all cells on the brain (Zlokovic, Berislav V. 187). Their chief role is immune defense. Being the local macrophage cells, they function as a line of defense in the CNS. Like astrocytes, they are distributed across the CNS in non-overlapping regions. Their role in immune defense is critical in overall brain maintenance. Microglia are designed to constantly scavenge for damaged and dead synapses and neurons, as well as infectious agents. Since dead matter can be potentially fatal within the CNS, microglia are very sensitive. They can pick up very tiny pathological changes. Their extreme sensitivity can be traced to the presence of special potassium channels that react to the smallest changes in extracellular potassium. Academic literature indicates that microglia are key in sustaining normal brain functions and wellbeing. Apart from surveying for unwanted material, microglia also track neuronal functions via direct somatic contacts as well as to apply neuroprotective reactions when necessary.
The primary constituents of the CNS, which are the brain and the spinal cord, cannot be assessed directly by the body’s pathogenic mechanisms die to BBB endothelial cells. While the BBB prevents a majority of infections from reaching vulnerable part of the CNS, some infectious agents can occasionally pass. When this occurs, the microglial cells react quickly to destroy infectious agents and decrease inflammation. If not destroyed instantly, infectious agents can damage sensitive neural tissue and cause catastrophic health issues. Very few antibodies have the ability to cross the BB. Therefore, microglia must have the capacity to recognize foreign agents, engulf them, and serve as antigen-presenting cells that activate T-cells.
Microglia play an important role in constant surveillance of the brain parenchyma. They sculpt and coordinate neural circulates to maintain a healthy brain while responding rapidly to create reactive phenotypes during instances of brain damage and infection. When microglia is activated, it has the ability to function in various ways. They can accelerate the clearance of damage by phagocytosis. They can also increase progression of disorders by discharging molecules that can introduce neuro-inflammatory states. Microglia can also react to inflammatory diseases of the periphery.
At the subcellular plane, the structural integrity of the BBB is maintained by the tight junctions. The main types of junctions are the tight junctions and the adheren junctions. Tight junctions seal the endothelial cells to form an unbroken tubular arrangement while adheren junctions initiate and maintain the endothelial cell contact. In endothelial cells of the periphery, the tight junctions are placed apically separate from the adheren junction. However, in the BBB endothelial cells, tight and adheren junctions are adjacent, creating the junction complex between neighboring endothelial cells. By component, the complex junction contains accessory cytoplasm proteins and transmembrane proteins which exist on the apical side of the endothelium layer. It is inside the junction complex that the transmembrane proteins interact directly. On the other hand, transmembrane proteins are anchored by cytoplasmic proteins to the actin cytoskeleton. The high occlusion of the cleft by the tight junction complex contributes to the high electrical resistance within the brain endothelium.
Tight Junctions (TJs)
Tight junctions consist a sequence of intramembranous strands that stretch across the inter-cellular cleft of contiguous endothelial cells (Zlokovic, Berislav V. 179). By composition, they comprise three major transmembrane proteins namely junction adhesion molecules, occluding, and claudin. However, there are other cytoplasm accessory proteins such as cingulin and zonula occluden proteins. The cytoplasm proteins are responsible for binding the membrane proteins to tactin, which is a key cystoskeleton protein. In particular, tactin maintains the functional and structural integrity of the endothelium. These phosphoproteins are the main components of tight junctions and the pare-cellular barrier of the BBB. Not only do they mediate the adhesion between cells through hemophilic means but also regulate BBB permeability and migration of leucocytes. Based on the location in the upper part of the plasma membrane, tight junctions provides the first layer of prevention against para-cellular diffusion of solutes into the brain. They are particularly crucial in the regulation of lateral diffusion between basolateral and apical plasma membrane domains. This aids in the maintenance of plasma membrane protein and lipid polarity.
Claudin, which is a major transmembrane protein that makes up tight junctions, contains four membrane-spanning areas with two intracytoplasmic termini and two extracellular loops. On the other hand, occludin represents a four transmembrane segment containing three intracytoplasim domains and two equal extracellular loops. Junctional adhesion molecules are classified within the immunoglobulin family and share a transmembrane domain with two big loops. Junction adhesion molecules are explicitly involved in fashioning the physiological function of the junctions. Occludins attach to zonula occludens protein 1 via the c-terminal in endothelial cells. Compared to the periphery, there is a higher expression of occludin in the brain. The zonula occludens protein 1 is also more continuous in the brain than the periphery. Even so, high levels are not adequate to guarantee high-resistance in junctions. In response to this, there exist other level of regulation for determining junction properties. Some scholar suggest that that the junctional proteins’ state of phosphorylation could serve a role in their activity. Preliminary experiment hint that occludin appears to be more phosphorylated in cultured endothelial cells of the BBB as compared to those of the periphery. Additionally, proteins such as p100 and p120 may be phosphorylated under various stimuli that affect the permeability of tight junctions.
Adherens junctions are primarily involved in the mediation of endothelial cells and the control of para-cellular permeability (Zlokovic, Berislav V. 179). They are mainly made up of calcium –dependent protein cadherin. This protein links with the actin cytoskeleton through intermediary proteins to create adhesive properties between cells. Tight junction and adheren junction components, especially the zonula occludens and catenins interact and regulate permeability through the endothelium.
Adherence junctions are important in the sustenance of the tight junctions and the junctional complex. This is connected to their role of keeping adjacent cells together. The main elements of the adheren junction embroil transmembrane glycoproteins of the cadherin family. These mainly entail vascular endothelium cadherin which have the capacity to create homotypic adhesive complexes with neighboring cells in the presence of calcium. Glycoproteins are connected to the cytoskeleton via a cytoplasmic plaque with the help of anchor proteins from the armadillo family. These include but are not limited to p120ctn, g-catenin, and bb-catenin. These proteins contain armadillo repeat which represents a long amino acid sequence that facilitates binding to the cadherins.
Apart from tight and adheren junctions, there are other junctions implicated in the role of the BBB. For instance, the gap junctions are communicating junctions that facilitate the direct passage of molecules between cells. By composition, gap junctions are consist of various transmembrane channels referred as pores which are organized in a tightly packed arrangement. The amount of gap junctions that are shared between a pair of cells can vary. Typically, each gap junction channels is composed of two hemi-channels, one of which is located in the membrane of each cell. The half channels link together and create a bridge between the cells to form a channel spanning the cell membranes of both cells. Each of the half channels formed is referred as a connexion, each of which consists of six symmetrical integral membrane protein units. This implies that every channel is made up of 12 protein units.
Intercalated disks are made up of three distinct types of junctions namely intermediate filaments that anchor desmosomes, actin filaments that anchor adherens junctions, and gaps junctions. Gap junctions are especially valuable in metabolic and electrochemical coupling. Some molecules that mau cross gap junction channels include regulatory proteins, ions, and metabolites such as calcium ions and cyclic adenosine monophosphate. The type of gap junction involved dictates what types of molecules can pass evenly across both directions. While some gap junctions will cross faster in one direction than the second direction, others may adopt an opposite pattern. Channels in gap junctions may not always remain open. Some may close at some point. This fluctuation is enabled by calcium ions which stimulate reversible conformational alterations in the connxin molecules.
In the tissues of the periphery, nutrients and metabolic waste products are able to cross freely across the intercellular cleft. This is important as they are needed in the molecular exchange between the blood and tissues. The fact that that they can cross the intercellular cleft is enabled by the junctions of the periphery which are sufficiently tight to obstruct the flow of plasma proteins but permeable enough to allow the passage of small hydrophilic solutes. Nevertheless, the para-cellular pathway between the brain and blood is very restricted compared to that of the periphery. Indeed, in the brain, transport is facilitated by special transport systems within the endothelial membranes. There are more than 20 transporters that play the role of uptake. These are called uptake transporters and comprise nucleosides, amino acids, glucose, and various organic anions and cations.
A majority of transporters of the BBB, including the GLU-1 glucose carrier facilitate transfer but do not require energy (Zlokovic, Berislav V. 180). They move solutes down through an electrochemical gradient. In contrast, others need energy to transport substances against a gradient. The energy can be obtained directly from active transport or through coupling with other molecules to enable the use of favorable concentration gradients. Some transporter excist in the luminal or apical and the basal or abluminal membranes of the endothelium. Others solely exist in one membrane to allow for the potential for vectorial or directional transport. The sodium-dependent glutamate transporters seem to be present principally in the abluminal membrane and their critical role is to facilitate the removal of glutamate from the brain. Albeit the expression of brain endothelial transporter is well recognized, the basal or apical distribution remains unclear in literature. This is partly because its kinetics of transport are complicated and hard to model. Furthermore, the location of relevant proteins in the cell, such as enzymes, may play a major role in solute flux.
Some uptake transporters of the BBB can work bi-directionally. Nonetheless, scholars have identified several families of transporters that can transport solutes out of the endothelial cells of the BBB, often consuming energy. Such transporters include the ABC family (Abbott et al. 20), the Breast Cancer Resistance Protein, and the Multidrug Resistance Related Proteins. While their roles physiology remain unclear, their potential in restricting the entry of harmful and toxic lipophilic agents in the CNS is evident. Scholars agree that they may have other functions, especially relating to drug delivery because of their potential to reduce or block entry of drug molecules.
Disruption of Blood Brain Barrier (neurological disease)
The disruption of the Blood Brain Barrier can occur due to a range of disorders, including Multiple Sclerosis, stroke, and epilepsy. In these conditions, BBB disruption emerges an element of pathology. In some disorders, such as Alzheimer’s disease, the materialization and extent of breakdown is more controversial and a growing area of research (Zlokovic, Berislav V. 188). When the function of BBB is disrupted, the main consequences are edema, dysregulation, and neuro-inflammation, which is a precursor to neuronal degeneration, increased intracranial pressure, and neuronal dysfunction. Even so, the precise mechanisms that underlie BBB disruption and its role in the development and progression of neurological conditions is not well understood. The phrase “BBB disruption” invokes images of the obliteration of a physical wall, interfering with the flow of molecules from the blood to the brain. Be that as it may, the BBB does not constitutes a physical wall but a sequences of physiological traits, the change of which is bound to significantly affect neurological development and health. For example, the disruption of GLUT-a glucose transport across the BBB can lead to seizure. By the same token, the dysfunction of the LAT1 amino acid transport can lead to manifestation of autism spectrum disorder. One of the most common disorders originating from BBB disruption that has been studied extensively is multiple sclerosis. BBB dysfunction is a key trait of the multiple sclerosis. The time course of leakage in patients with multiple sclerosis has been investigated using dynamic contrast-enhanced MRI. Barrier leakage has been observed in new lesions. MRI evidence shows that BBB permeability is a precursor to the formation of lesions. However, some lesions occur before the barrier dysfunction. In patients with stroke, BBB disruption materializes through the leakage of nonspecific molecules and structural changes in tight junctions. Generally, the disruption of the Blood Brain Barrier leads to some form of neurological issue.
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