ReviewStructure and function of the blood–brain barrier
Introduction
Neurons within the central nervous system (CNS) communicate using a combination of chemical and electrical signals, and precise regulation of the local ionic microenvironment around synapses and axons is critical for reliable neural signalling. It has been argued that this was one of the chief evolutionary pressures leading to the development of mechanisms for maintaining the homeostasis of the neural microenvironment (Abbott, 1992). Barrier layers at the key interfaces between blood and neural tissue play a major role in this regulation (Abbott et al., 2006).
All organisms with a well developed CNS have a blood–brain barrier (BBB) (Abbott, 2005). In the brain and spinal cord of mammals including humans, the BBB is created by the endothelial cells that form the walls of the capillaries. The combined surface area of these microvessels constitutes by far the largest interface for blood–brain exchange. This surface area, depending on the anatomical region, is between 150 and 200 cm2 g- 1 tissue giving a total area for exchange in the brain of between 12 and 18 m2 for the average human adult (Nag and Begley, 2005).
A second interface is formed by the epithelial cells of the choroid plexus facing the cerebrospinal fluid, which constitute the blood–cerebrospinal fluid barrier (BCSFB). The CSF is secreted across the choroid plexus epithelial cells into the brain ventricular system (Brown et al., 2004), while the remainder of the brain extracellular fluid, the interstitial fluid (ISF), is derived at least in part by secretion across the capillary endothelium of the BBB (Cserr et al., 1981, Cserr and Patlak, 1992, Abbott, 2004, Dolman et al., 2005). ISF and CSF are free to communicate at several locations; different experimental studies have estimated the contribution of ISF to CSF as 10–60% (Milhorat et al., 1971, Davson and Segal, 1995). The secretion of CSF and ISF is driven by the ionic and osmotic gradient created by the Na+,K+-ATPase, expressed in the abluminal membrane of the BBB endothelium and the apical membrane of the choroid plexus epithelium, resulting in water movement and volume flow (Abbott, 2004).
The third interface is provided by the avascular arachnoid epithelium, underlying the dura, and completely enclosing the CNS; this completes the seal between the extracellular fluids of the central nervous system and that of the rest of the body (Abbott et al., 2006). Although the arachnoid also forms a barrier layer, its avascular nature and relatively small surface area mean that it does not represent a significant surface for exchange between the blood and the CNS (Fig. 1) (Kandel et al., 2000).
At all three interfaces, the barrier function results from a combination of physical barrier (tight junctions between cells reducing flux via the intercellular cleft or paracellular pathway), transport barrier (specific transport mechanisms mediating solute flux), and metabolic barrier (enzymes metabolizing molecules in transit). The barrier function is not fixed, but can be modulated and regulated, both in physiology and in pathology (Abbott et al., 2006).
The BBB not only provides a stable environment for neural function, but also by a combination of specific ion channels and transporters keeps the ionic composition optimal for synaptic signalling function. Thus the concentration of potassium in mammalian plasma is approximately 4.5 mM, but in CSF and brain ISF this is maintained at ∼ 2.5–2.9 mM, in spite of changes that can occur in plasma [K+] following exercise or a meal, imposed experimentally, or resulting from pathology (Bradbury et al., 1963, Hansen, 1985). Ca2+, Mg2+ and pH are also actively regulated at the BBB and BCSFB (Somjen, 2004, Jeong et al., 2006, Nischwitz et al., 2008).
Blood plasma contains high levels of the neuroexcitatory amino acid glutamate which fluctuate significantly after the ingestion of food. If glutamate is released into the brain ISF in an uncontrolled manner, as for example from hypoxic neurons during ischemic stroke, considerable and permanent neurotoxic/neuroexcitatory damage can occur to neural tissue. Since the central and peripheral nervous systems use many of the same neurotransmitters, the BBB also helps to keep the central and peripheral transmitter pools separate, minimising ‘cross-talk’ (Abbott et al., 2006, Bernacki et al., 2008).
The BBB prevents many macromolecules from entering the brain. The protein content of CSF is much lower than that of plasma, and the individual protein composition markedly different (Table 1). Plasma proteins such as albumin, pro-thrombin and plasminogen are damaging to nervous tissue, causing cellular activation which can lead to apoptosis (Nadal et al., 1995, Gingrich and Traynelis, 2000, Gingrich et al., 2000). Factor Xa is present in the brain, which converts pro-thrombin to thrombin, and the thrombin receptor PAR1 is widely expressed in the CNS. Similarly tissue plasminogen activator is present in central nervous tissues and converts plasminogen to plasmin. Thrombin and plasmin if present in brain ISF can initiate cascades resulting in seizures, glial activation, glial cell division and scarring, and cell death (Gingrich and Traynelis, 2000). Thus leakage of these large molecular weight serum proteins into brain across a damaged BBB can have serious pathological consequences. One of the few proteins to have a higher concentration in CSF than in plasma is cystatin-C (Table 1), which is synthesised locally within the CNS (Reiber, 2001). Cystatin-C is a serine protease inhibitor and a high concentration in CSF may be a protective measure against micro-leaks in the BBB which continually and spontaneously occur and would otherwise allow plasma components to seep into the brain.
The BBB functions as a protective barrier which shields the CNS from neurotoxic substances circulating in the blood. These neurotoxins may be endogenous metabolites or proteins, or xenobiotics ingested in the diet or otherwise acquired from the environment. A number of ABC energy-dependent efflux transporters (ATP-binding cassette transporters) actively pump many of these agents out of the brain (see below). The adult CNS does not have a significant regenerative capacity if damaged and fully differentiated neurons are not able to divide and replace themselves under normal circumstances. There is a continuous steady rate of neuronal cell death from birth throughout life in the healthy human brain, with relatively low levels of neurogenesis (Lim et al., 2007). Any acceleration in the natural rate of cell death resulting from an increased access of neurotoxins into the brain would become prematurely debilitating.
The BBB has low passive permeability to many essential water-soluble nutrients and metabolites required by nervous tissue. Specific transport systems therefore are expressed in the BBB to ensure an adequate supply of these substances. The differentiation of the endothelium into a barrier layer begins during embryonic angiogenesis (see below) and in the adult is largely maintained by a close inductive association with several cell types, especially the endfeet of astrocytic glial cells. This induction promotes the upregulation of tight junction proteins and the development of polarity in the endothelial cells arising from the differential expression of specific transporter proteins in the luminal and abluminal membranes (Abbott et al., 2006, Wolburg et al., 2009). Pericytes, microglia and nerve terminals are also closely associated with the endothelium, and play supporting roles in barrier induction, maintenance and function (Abbott et al., 2006, Shimizu et al., 2008, Nakagawa et al., 2009). The cell associations at the BBB are shown in Fig. 2.
In summary the CNS barriers together provide the stable fluid microenvironment that is critical for complex neural function, and protect the CNS from chemical insult and damage.
Section snippets
BBB tight junctions
The BBB to macromolecules and most polar solutes is created by tight junctions (TJs) between the cerebral endothelial cells, the choroid plexus epithelial cells and the cells of the arachnoid epithelium. Extremely tight ‘tight junctions’ (zonulae occludentes) are a key feature of the BBB and significantly reduce permeation of polar solutes through paracellular diffusional pathways between the endothelial cells from the blood plasma to the brain extracellular fluid (Begley and Brightman, 2003,
Transport across the BBB
Several potential routes for permeation across the BBB are shown in Fig. 4.
Development of the blood–brain barrier
The BBB develops during fetal life and is well formed by birth, especially to proteins and macromolecules (Olsson et al., 1968, Tauc et al., 1984, Saunders, 1992, Moos and Møllgård, 1993, Keep et al., 1995, Preston et al., 1995, Saunders et al., 2000, Ballabh et al., 2004). In the mouse the BBB begins to form between E11 and E17, by which time identifiable tight junctions are present. The presence of TJs will tend to restrict trans-endothelial movement of polar solutes and macromolecules. In
Blood–brain barrier in pathology
There is a growing list of CNS pathologies involving an element of BBB dysfunction, including multiple sclerosis (Correale and Villa, 2007); hypoxia and ischemia (Kaur and Ling, 2008); edema (Rosenberg and Yang, 2007); Parkinson's disease and Alzheimer's disease (Desai et al., 2007, Zlokovic, 2008); epilepsy (Remy and Beck, 2006); tumours (Bronger et al., 2005); glaucoma (Grieshaber and Flammer, 2007) and lysosomal storage diseases (Begley et al., 2008) (Table 5). The barrier dysfunction can
Blood–brain barrier regulation
It is increasingly recognised that the BBB is a dynamic system, capable of responding to local changes and requirements, and able to be regulated via a number of mechanisms and cell types, in both physiology and pathological conditions. Such regulation includes changes in tight junction function (Balda and Matter, 2009), and in expression and activity of many transporters and enzymes (Abbott et al., 2006, Dauchy et al., 2009). Regulation is an efficient means of matching the activities of the
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