The molecular constituents of the blood-brain barrier

Abstract

The blood-brain barrier (BBB) maintains the optimal microenvironment in the central nervous system (CNS) for proper brain function. The BBB comprises specialized CNS endothelial cells with fundamental molecular properties essential for the function and integrity of the BBB. The restrictive nature of the BBB hinders the delivery of therapeutics for many neurological disorders. In addition, recent evidence shows that BBB dysfunction can precede or hasten the progression of several neurological diseases. Despite the physiological significance of the BBB in health and disease, major discoveries of the molecular regulators of BBB formation and function have occurred only recently. This review highlights recent findings describing the molecular determinants and core cellular pathways that confer BBB properties on CNS endothelial cells.

Keywords: blood–brain barrier.

Figure 1. The functional BBB is dependent on the neurovascular unit

The blood-brain barrier (BBB) is localized at central nervous system (CNS) microvessels, comprising of a single layer of continuous, nonfenestrated endothelial cells. Surrounding the aluminal surface of the CNS endothelial cells are the basement membrane, pericytes, and astrocyte endfeet, collectively known as the neurovascular unit (NVU). The BBB properties are not intrinsic to CNS endothelial cells but require the continuous functional interactions with the NVU.

Figure 2. The four fundamental molecular properties of CNS endothelial cells that contribute to BBB integrity and function

(1) Specialized tight junction complexes between endothelial cells prevent paracellular flux. (2) CNS endothelial cells have low rates of transcytosis, limiting transcellular flux. (3a) CNS endothelial cells mediate the selective uptake of nutrients and molecules from the blood using selective influx transporters and (3b) efflux of toxins against their concentration gradient with ATP-dependent selective efflux transporters. (4) The low expression of leukocyte adhesion molecules (LAMs) contributes to the low level of immune surveillance in the CNS.