Event Abstract

Structure and function of the blood-brain barrier

  • 1 King’s College London, BBB Group, Pharmaceutical Science Division, United Kingdom

Reliable neural signalling within the central nervous system (CNS) relies on precise ionic movements across cell membranes that generate electrical signals at synapses and in axonal conduction. There is evidence that a major pressure driving evolution of CNS blood-tissue barriers was the selective advantage given by fine control (homeostasis) of the brain ionic microenvironment. Three main barrier sites contribute to this homeostasis: the endothelial cells of brain microvessels forming the blood-brain barrier (BBB), the epithelial cells of the choroid plexus secreting cerebrospinal fluid and forming the blood-CSF barrier (BCSFB), and the epithelial cells of the arachnoid membrane at the brain surface (1). The spinal cord has equivalent barriers in internal vessels and in surface arachnoid, but lacks choroid plexus tissue. In addition to ionic homeostasis, CNS barriers regulate blood-brain molecular traffic, separate central and peripheral neurotransmitter pools, and limit the brain entry of plasma proteins and circulating leukocytes. At the BBB, the endothelial cells do not act alone, but function within a well organised 'neurovascular unit' (NVU) (Fig. 1), a modular structure integrating the local neuronal population and its associated astrocytic glia with the cells forming the microvascular tube providing blood flow, the endothelium and pericytes, and in arterioles also smooth muscle (2). Microglia, the resident immune cells of the CNS, are associated with the NVU, in quiescent state in normal physiology, but becoming activated in pathology.

At each barrier site, tight junctions between cells of the monolayer form a physical barrier by significantly reducing passive diffusion through the intercellular cleft (paracellular pathway), forcing any molecular traffic to be predominantly across the cell (transcellular) (Fig. 2). Small lipophilic molecules and gases such as oxygen and carbon dioxide can diffuse across the barriers via the lipid membranes. Specific solute carriers (SLCs, also called transporters) in apical and basolateral membranes control the influx of small polar solutes needed by the brain (nutrients such as glucose and amino acids) and the efflux of many waste products. Several members of the ATP-binding cassette (ABC) transporter family help exclude many potentially toxic compounds present in the circulation, derived from the diet or the environment. ABCs present at the BBB include P-glycoprotein (P-gp, ABCB1), breast-cancer resistance protein (BCRP, ABCG2) and several multidrug-resistance related proteins (MRPs, ABCC family); the choroid plexus also expresses ABCs, although using a different repertoire of transporters. Since many drugs of potential value in treating CNS disorders are substrates for ABCs, this complicates drug therapy of the brain. The BBB and BCSFB have low permeability to larger molecules such as peptides and proteins, but some smaller peptides such as beta-amyloid (Aβ) may be substrates for uptake and/or efflux transporters. Two classes of vesicular transport mediate limited entry of larger molecules: receptor-mediated transcytosis (RMT) and adsorptive-mediated transcytosis (AMT), the former requiring specific interaction with surface receptors before endocytosis, the latter involving less specific surface-charge interactions between cationic molecules and the barrier cell membrane followed by endocytosis. Finally the barrier layers act as ‘enzymatic barriers’, by a combination of cell surface and intracellular enzymes that break down certain molecules in transit, further reducing entry of many neuroactive and neurotoxic agents.

Several features of the BBB make this endothelial layer distinct from the endothelium of non-brain microvessels, including the tightness of the tight junctions, the strongly expressed cellular polarity with distinct apical and basal cell membrane function, the complex pattern of SLC/ABC transporter expression, the down-regulation of vesicular transport, and the upregulation of barrier enzymes. The differentiation of this unique BBB phenotype begins at the time of brain vascularization in the embryo, with both angiogenesis and barrier formation apparently controlled by the Wnt-beta catenin signalling pathway (3). This involves inductive influences from the developing brain, initially from the early neuronal-glial precursor cell population, later from more fully differentiated cell types including astrocytes and pericytes. The inductive maintenance of the BBB phenotype by associated cells is crucial to healthy function in the adult, and damage or dysfunction of BBB-associated cells especially of astrocytes (e.g. in brain tumours) can lead to acute or chronic disturbance of BBB function.

Until recently, the BBB was treated as a relatively homogeneous structure. However, it is increasingly realised that BBB function can differ along the length of the vascular tree, and also in different brain regions. One important distinction is between the barrier role of the largest fraction of the blood-brain interface, created by the highly branching capillary network, and the specific role of the smaller surface area created by the first collecting vessels, the post-capillary venules. The capillaries are generally not a site for brain entry of circulating leukocytes, which may contribute to the protective role of the BBB by limiting inflammatory events within the brain. However, the post-capillary venules (PCV) are different, having leakier tight junctions and responding more vigorously to infectious and inflammatory conditions. In mild inflammation, leukocytes may gain access across the endothelium of the PCV either via tight junctions or through the cells (Fig. 2), but be held within the expanded perivascular space by the properties of the basement membranes (basal laminae) of the endothelial cells and of the perivascular astrocytic end feet. This creates a 'perivascular niche', an important reservoir for leukocyte invasion of the CNS. Many severe CNS disorders are associated with significant leukocyte entry beyond the astrocytic (or 'parenchymal') basement membrane.

In addition to regional specializations, it is increasingly recognised that the BBB at capillary and postcapillary venule level can be modulated, both acutely (over seconds to minutes) and chronically (over months to years). Modulatory influences can come from cells of the NVU or from the blood (Fig. 3). There is considerable evidence for modulation of the tight junctions by inflammatory mediators acting individually and in concert, causing significant paracellular leak; when mild this will disturb local CNS ion and small solute homeostasis, but in more severe conditions it will allow leakage of plasma proteins such as albumin, which can lead to neuronal cell death. Modulation of the transport function of the BBB is increasingly documented, for example up- and down-regulation of P-gp by inflammatory agents acting through nuclear transcription factors. Changes in both transporter expression and activity can be involved. The earlier literature also suggested that BBB vesicular mechanisms can be upregulated in inflammation, but this has been less well investigated. Changes in enzyme expression can also occur in response to endogenous and exogenous chemical influences. Some aspects of acute BBB modulation can be seen as protective, for example facilitating limited leukocyte and growth factor entry to fight infection and stimulate repair, and upregulating efflux transporters to help compensate for a more leaky BBB. However, chronic BBB opening can have serious pathological sequelae.

The plasticity of BBB function that is emerging, whether physiological, pathological, or drug-induced, further complicates attempts to predict drug pharmacokinetics in brain, since drug treatments are generally given in the context of some pathology, and will meet conditions at the BBB that can change significantly during a treatment regime. As more is learned about the BBB modulation in physiology and pathology, it may be possible to develop biomarkers for specific phases of the process, so that BBB function can be monitored and drug treatments adjusted accordingly. However, the relative inaccessibility of the BBB, with biopsy for assessing function largely ruled out, will certainly make diagnostic development difficult. Careful screening of plasma and leukocyte proteomics may offer the best opportunities for diagnostic biomarkers for the BBB.

In summary, the structure and function of the BBB within the neurovascular unit control molecular exchange and cellular traffic at this major blood-CNS interface. The BBB phenotype in the brain endothelium is induced in the embryo and maintained in the adult by interaction with associated cell types, and can be modulated in physiology and pathology. There are important implications for drug delivery and neurotoxicology.

The neurovascular unit
Cells associated with the brain endothelium
Routes across the brain endothelium


1. Abbott N.J. et al. (2010) Structure and function of the blood-brain barrier. Neurobiol. Disease 37:13-25.

2. Abbott N.J. et al. (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nature Rev. Neurosci. 7:41-53.

3. Liebner S. et al. (2008) Wnt/beta-catenin signaling controls development of the blood-brain barrier. J. Cell Biol. 183: 409-417.

Conference: Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU, Brussels, Belgium, 11 Feb - 12 Feb, 2010.

Presentation Type: Oral Presentation

Topic: Presentations

Citation: Abbott NJ and Yusof SR (2010). Structure and function of the blood-brain barrier. Front. Pharmacol. Conference Abstract: Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU. doi: 10.3389/conf.fphar.2010.02.00002

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Received: 22 Feb 2010; Published Online: 22 Feb 2010.

* Correspondence: N. J Abbott, King’s College London, BBB Group, Pharmaceutical Science Division, London, United Kingdom, joan.abbott@kcl.ac.uk