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Cerebral capillaries are fundamentally similar to those of other tissues, but there are important differences. There is a paucity of cytoplasmic vesicles in the endothelial cells, and the tight junctions between the endothelial cells differ from those of other tissue capillaries. In addition, astro¿½cytic foot processes surround each capillary. The lumen is lined by endothelial cells which display oval or elongated nuclei located in the thickened part of the capillary wall. The cytoplasm contains the usual set of organelles, of which mitochondria are the most abundant. Complex membrane-bound structures, the Weibel-Palade bodies, are difficult to find. Cytoplasmic vesicles are scarce and fewer than in most other capillaries. The structure of the interendothelial connections is variable, but in general the adjacent cell membranes are parallel, and, towards the luminal end, the outer leaflets fuse to form tight junctions (zonulae occludentes).
The endothelial cytoplasm is richly endowed with enzymes, including adenosine tri¿½phosphatase, nicotinamide adenine dinucleotide, monoamine oxidase, acid and alkaline phos¿½phatases, various dehydrogenases, DOPA decarboxylase and glutamyl transpeptidase. The wealth of these enzyme systems reflects the unique role played by the cerebral endothelium in the blood-brain barrier. Moreover, differences in the intensity of various hydrolytic enzymes at the luminal and abluminal cell membrane strongly indicate the polarity of endothelial function in the control of the blood-brain interface. Outside the endothelium lies a continuous basal lamina or basement membrane approximately 40-50 nm thick and composed of an admixture of substances, including type IV collagen, heparan sulphate proteoglycan, laminin and entactin. Astrocytic foot processes abut onto capillaries, forming a complete envelope in most cases :occasionally other cells may have direct contact with the basal lamina. Pericytes are completely surrounded by a duplication of the basement membrane, and are frequently seen extending their processes around the capillary; their cytoplasm contains many lysosome-like bodies. The origin and function of pericytes remain to be established, although the view that they could give rise to microglial cells has gained some support .
Arterioles and small arteries differ from capillaries not only in their larger size, but also by the presence of smooth muscle cells in their walls. Outside the endothelium, one or two layers of smooth muscle cells are transversely orientated and sandwiched between thick basal laminae. Venules resemble large capillaries and the transition between the two types of vessel is difficult to identify.
The blood-brain barrier
The concept of a blood-brain barrier was first based upon the observation that intravenously injected vital dyes, like Evans (azovan) blue and trypan blue, entered and stained various organs, but not the brain. Later, ultrastructural studies with electron-dense tracers, such as horseradish peroxidase or lanthanum, demonstrated that tracers do not penetrate the interendothelial cell junctions in the brain, neither are they carried across the endothelial cell by vesicular transport. The morphological basis for the blood-brain barrier appears to reside in two features of endothelial cells: the presence of tight junctions and the paucity of cytoplasmic vesicles. The oversimplified single-membrane model, however, is no longer accepted; intercellular tight junctions, intracellular enzyme systems and the two endothelial cell membranes all contribute to the barrier effect. It has been demonstrated in vitro that astrocytic foot processes, unique to cerebral capillaries, could contribute to the barrier. Astrocytes are essential for the expression of the endothelial enzymes which play a role in transport mechanisms and for the induction of barrier properties in vitro.
The blood-brain barrier does not pertain in all parts of the mammalian brain: a few, relatively small and usually periventricular structures are freely permeable to vital dyes and electron-dense tracers. These structures include the area postrema, median eminence, subcornmissural organ, pineal gland, subfornical organ, supraoptic crest and neurohypophysis. The blood vessels in these areas have ultrastructural, enzymatic and permeability features which are different from those in other areas of the brain.
It has been realised that the blood-brain barrier is more a regulatory interface between the blood flow and the cerebral parenchyma than a simple rigid physical barrier.The passage of a particular substance across the blood-brain barrier may depend upon various factors, including its lipid solubility, electrical charge, molecular size, dissociation constant, affinity for a carrier molecule and the nature of the substance in relation to the capacity of the blood-brain barrier for active transport.
The function of the blood-brain barrier is threefold. First, it prevents or hinders the entry of most water-soluble substances into the brain; the permeation rates are usually determined by lipid solubility. Secondly, the blood-brain barrier promotes the transport of certain materials, including some hexoses and several amino acids, by stereo-specific carrier transport systems which are present in the cerebral endothelium. The transport of various materials across the blood-brain barrier has been recently reviewed. Thirdly, the blood-brain barrier plays an important role in the volume regulation of the central nervous system. This is achieved by two mechanisms which limit the bulk flow of water across the blood-brain barrier: these are the low hydraulic conductivity of capillaries and the high osmotic activity of the major solutes.
THE CHOROID PLEXUS
The choroid plexus is composed of a vascular fold of the pia mater and an epithelial layer derived from the ependymal lining. There are four choroid plexuses, one in the medial wall of each lateral ventricle and one each in the roofs of the third and fourth ventricles. They have clearly defined attachments to the ventricular wall and their free edges are invaginated into the ventricles. The surface area of the choroid plexus is greatly increased by the many fronds, which in turn consist of tiny villous processes. The arteries supplying the choroid plexus branch out into capillaries, one for each villus, which then join to form a vein.
The epithelium consists of a single layer of cuboidal cells mounted on a basement membrane; in a few areas, however, pseudostratification or even true stratification may occur. Choroid plexus epithelium can be identified immunocyto¿½chemically by the presence of carbonic anhydrase in the cytoplasm; this enzyme probably plays a role in the production of cerebrospinal fluid (CSF). The round or oval nucleus of the cell is usually centrally located in the cytoplasm, which has the usual complement of organelles. Mitochondria are particularly numerous and are mainly in the apical portion of the cell: they provide the energy necessary for the active transport carried out during production of the CSF. Smooth and coated vesicles of various sizes are seen throughout the cytoplasm and these take part in the transport of materials. The apical surface of the epithelial cell is greatly increased in area by masses of microvilli and occasional cilia which tend to be grouped together. The lateral plasma membranes are bound together by complex connections: by tight junctions (zonulae occludentes) at the apical end, by zonulae adhaerentes, and by intricate infoldings at the basal end. Occasional phagocytes, the epiplexus or Kolmer cells, are seen on the surface of the choroid plexus epithelium; they may play a role in keeping this surface free of debris.
The fibrovascular core of the choroid plexus supporting the epithelium contains arachnoid cells; whorls of collagen fibres in the fibrous stroma become calcified with advancing age. Blood vessels of various sizes include small arteries, arterioles, capillaries and venous sinuses. Capillaries in the villi are fenestrated and their endothelial lining is very thin.
Functions of the choroid plexus
The main function of the choroid plexus is the production of the CSF, although a proportion of the CSF estimated to be 10-20%, is derived from extrachoroidal sources.In man, approximately 500-700 ml is produced every day; of this only 140 ml can be accommodated at any one time: 25-30 ml in the ventricles and the rest in the sub¿½arachnoid space. Although it has been disputed whether the CSF is the result of passive dialysis or active secretion, evidence now favours the latter mechanism. Factors which are involved in the formation of CSF include pressure, serum osmolality, temperature, age, innervation of the plexus and prostaglandins. The enzyme systems of the choroid plexus and various theories of CSF production have been recently reviewed.
The choroid plexus may also take part in the absorption of materials as demonstrated in experi¿½mental animals, but this function has not been unequivocally confirmed. An estimated l0% of the CSF may be absorbed by the choroid plexus.
1. Introduction to the Blood-Brain Barrier: Methodology, Biology and Pathology [Paperback]:William M. Pardridge MD (Editor)
The blood-brain barrier serves to protect the brain from toxic substances whilst simultaneously allowing access to essential nutrients and chemical signals. At the interface between brain and body, knowledge of the blood-brain barrier forms an essential component in the complete understanding of a large proportion of medical disciplines. Nevertheless, it seems that ignorance of both the biology of this important membrane and the methodology suitable for its investigation still remains an impediment to progress in many fields, including, for example, the development of new and efficacious neuropharmaceuticals, cerebrovascular disease, Alzheimer's disease, cerebral AIDS and brain tumours. This introduction for both researchers and clinicians across the medical sciences is intended to aid both those beginning work directly in this area and those wishing simply to be better informed when interpreting information where the blood-brain barrier may be involved. Advances in both methodology and biology are detailed in 50 chapters from international authorities.