The concept of an anatomical barrier separating blood and CNS first emerged from the studies of Goldmann (1913) who injected trypan blue into the venous system and observed that staining occurred throughout the body, whereas only the brain and CSF remained unstained. When he injected the dye into the CSF, the CNS tissue including the leptomeninges was strongly stained (Goldmann 1913). The role of this barrier system is to protect the brain from the outside environment and to maintain homeostasis of the brain (Dunn and Wyburn 1972; Abbott et al. 2010).

The special components of the BBB include capillary walls of endothelial cells, the basal membrane, and the perivascular layer of astrocytic end-feet. The BBB structures comprise a large surface area of 12–18 m² in adult humans for exchange of humoral and cellular factors across this barrier (Abbott et al. 2010).

The capillary wall consists of a monolayer of non-fenestrated endothelial cells which form the functionally most important part of the BBB (Fig. 2.3) (Süssmuth et al. 2008). Where the endothelial cells overlap, their cell membranes are connected to each other by tight junction protein complexes known as zonulae occludentes. The tight junctions of the BBB consist of different integral membrane proteins including occludins, claudins, junctional adhesion molecules, and associated cytoplasmatic proteins (Koziara et al. 2006). The presence of tight junctions and the lack of fenestrae severely restrict paracellular transport. Accordingly, any transport of molecules to the brain must occur via the transcellular route by passive diffusion or active transport, which may be adsorption mediated, carrier mediated, or receptor mediated (Koziara et al. 2006).

The endothelium basement membrane with a width of about 300–500 Ǻ offers no barrier to the passage of hydrophilic molecules such as ferritin (Brightman 1965). The vascular system and the neuronal system are not in direct contact but are covered by a sheath made up from processes of neuroglial cells including astrocytes and oligodendrocytes. The astrocytes dominate the transport route from capillaries to the neuron as seen in electron microscopy (Dunn and Wyburn 1972). Their processes variously called pedicles, end plates, or foot plates form a sheath covering the neurons, dendrites, axons, and capillaries. Another part of the satellite cells closely located to the neurons is the oligodendrocytes. Besides forming the myelin sheaths in the CNS, oligodendrocytes also take part in the formation of the glial sheath covering neuronal and vascular cells. A further element of the BBB is the extracellular space with a width of about 200 Ǻ that is labyrinthically ramifying between neurons, glial cells, and capillaries. It allows the unrestricted passage of ions and substances of colloidal size (Davson et al. 1970; Davson 1976).

Recent findings describe highly abundant AQP4 channels localized to perivascular and subpial end-foot membranes of astrocytes throughout the brain involved in regulation of extracellular space volume (Nagelhus and Ottersen 2013).