What is the BBB?

The role of this page is to give readers a basic understanding of the BBB and its function.  This is not by any means an exhaustive review of the BBB, and is largely based on what I consider important, I have also attached links to either reviews or relevent research papers.  For more in depth information (and for stuff I haven't mentioned), I recommend reading the reviews in the link section.  If any one can recommend other useful reviews let me know and I'll add the link.

Capillary beds in the periphery permit a free exchange of solutes between the blood and extracellular fluids.  In contrast the microvasculature of the  brain presents a dynamic and highly regulated interface between the blood and central nervous system (CNS).  This BBB protects the brain from fluctuations in the concentrations in blood solutes and from potentially neurotoxic substances.  The BBB also facilitates the exchange of nutrients and waste products between the brain and blood maintaining the optimal enviroment fo neurological function.

The primary barrier is at the level of cerebral capillary endothelium.  The BBB is in essence three barriers in one, a physical, transport, and metabolic barrier.  The physical barrier is supplied by the presence of tight junctions (TJ).  TJs, connect adjacent endothelial cells and hold them close together, limiting the size of the intercelluar cleft between cells.  This results in a high electrical resistance and a reduced paracellular diffusion for aqueous substances. 

The transport barrier consists of an interaction of nutrient transporters (such as amino acid transporters,) and efflux transporters (such as the ABC familiy).  Despite the reported low number of vesicles at the BBB, there is also an active endocytosis process.  This route is important for among other things iron regulation, and is used by viruses to enter the brain.

The metabolic barrier consists of a number of enzyme systems expressed in the endothelial cells that include peptidases, various CYP isoforms including CYP4X1, CY1A1, CYP1B1, CYP3A1, and CYP2E1.  Several conjugation enzyems such as glycolase 1 and 2, glutathione-s-transferase, and uridine diphosphate glucuronosyltransferase are also found at the BBB.

BBB endothelial phenotype is maintained by its local enviroment and also via the interaction with other cell types within the CNS.  The local enviroment is supplied on the basal side by the basement membrane (blue in the above figure).  Interaction with the basement membrane via various integrins helps maintain endothelial cell polarity.  The apical membranes are in contact with the blood.  Not only does this supply interactions with various blood components such as albumin, growth factors and blood cells, the flow of blood also supplies a shear stress essential for maintaining phenotype.  Two major CNS cell types involved in BBB function are astrocytes and pericytes.  Astrocytes ensheath the microvessels with their endfeet.  Adjacent endfeet may be linked via gap junctions enableing propogation of responses along a vessels length, potentially allowing regulation of local blood flow and metabolic trafficking.  Pericytes for years a very much understudied area of BBB research also play a vital role in BBB regulation and homeostasis.  They also have an important role in regulating fetal angiogenesis.

The role of pericytes, astrocytes, basment membrane, and other CNS cells in the regulation of BBB function has resulted in the concept of the "Neurovascular Unit" (NVU).  This concept helps explain the new findings of the dynamic nature of the BBB.  It also raises some interesting ideas about what the BBB really is, and what have we truly been studying over the last century?  Is the BBB different in various regions of the Brain?  Several interesting studies on astrocytes have recently shown that there are marked differences in astrocyte function from different brain regions, and also differences in astrocyte marker expression within a given brain region.  Are these differences functionally important?  The very specific regional effects of 3-chloropropanediol on astrocytes and subsequent BBB function would suggest that they are.  This makes sense as the individual environments within the brain for distinct brain regions could vary greatly depending on the regional functionality.  For example the substantia nigra will have more metabolic waste products related to dopaminergic signalling than the hippocampus.  Does this mean that there barriers are different as a consequence?  There has also been a tendancy in the field to think of the barrier for a particular region to be the same starting at the arterioles all the way through the venules.  However, there are compelling arguments for endothelial heterogeneity and thus barrier heterogeneity along the length of vascular beds. 

These are just some of the issues that are being discussed in the field at the moment.