Click on one of the boxes below to view the different structural features that form the blood-brain barrier.
The blood-brain barrier (BBB) is a dynamic interface between the peripheral circulation and the central nervous system (CNS). The basic element of the BBB, the neurovascular unit, is a complex structure composed of capillary endothelial cells (ECs), astrocytes, pericytes, and neurons. The anatomical integration of these cells and their interaction with additional perivascular elements form a selective diffusion barrier that regulates the movement of substances into and out of the CNS. Dysfunction of the BBB and the subsequent increase in infiltrating immune cells is associated with a multitude of neurological disorders including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.
Brain ECs are connected to one another by a multifaceted junction complex comprised of tight and adherens junctions. Tight junctions are composed of the integral membrane proteins Occludin, Claudins, and Junctional Adhesion Molecules (JAMs), which hold cells in close apposition by binding homotypically to their respective molecule in adjacent ECs. These proteins also associate with a number of cytoplasmic proteins that contribute to the integrity of tight junctions. Zona Occludens (ZOs) bind to the C-termini of Occludins, Claudins, and JAMs via their PDZ domains and help assemble these proteins at tight junctions. ZOs also bind to F-Actin through their C-terminus, anchoring the transmembrane proteins to the Actin cytoskeleton. The multimolecular junction complexes are also tethered to the Actin cytoskeleton via their association with Afadin/AF-6. Afadin/AF-6 is an F-Actin binding protein that associates with ZO-1, and Cingulin, a cytoplasmic homodimer that can interact with ZOs, Afadin/AF-6, F-Actin and other Cingulin molecules. The essential cell adhesion molecule at adherens junctions in the BBB is VE-Cadherin. VE-Cadherin is linked to the Actin cytoskeleton through its association with alpha- and beta-Catenin.
Junction complexes in brain ECs seal the paracellular spaces between adjacent ECs, thereby restricting the movement of molecules between the blood and the brain. Additionally, brain ECs lack the fenestrations that characterize ECs throughout the rest of the body. As a consequence, only small lipid soluble molecules are able to passively pass through the BBB. Movement of most other molecules across the BBB is dependent on the presence of transporter proteins in brain ECs. Influx transporters facilitate the uptake of essential molecules, such as glucose, amino acids, and ions, from the blood into the brain while efflux transporters clear metabolic wastes and neurotoxic compounds from the brain and prevent harmful substances from entering it. Main efflux transporter families include ATP-binding Cassette (ABC) transporters and Organic Anion Transport (OAT) systems. The expression levels of these transporter proteins vary between the luminal and abluminal membrane surfaces of the ECs, between cell types in the neurovascular unit, and between brain regions.
In the neurovascular unit, brain capillaries are surrounded by or closely associated with several different cell types including astrocytes and pericytes. Astrocytes are pivotal for the formation and maintenance of the BBB. They support the integrity of tight junctions and regulate the expression and localization of transporter proteins. These cells also link brain ECs to nearby neurons. Astrocytes and ECs bind to extracellular matrix (ECM) proteins of the basement membrane via ECM receptors, such as Dystroglycan and Integrins. Proteins of the ECM help regulate the integrity of the BBB. Many pathological states of the CNS rapidly alter the expression and proteolysis of ECM components, resulting in degradation of the basement membrane and disruption of the BBB. Pericytes are cells of microvessels that are localized to the abluminal membrane of ECs and wrap around the vessel. They are important for maturation and stabilization of EC contacts and astrocyte adhesion. Pericytes and ECs also share a common basement membrane. In areas where there is no basement membrane, pericytes and ECs are connected by direct peg and socket contacts that contain cell-to-cell junction proteins.
To learn more, please visit our Blood-brain Barrier Permeability Research Area.