Blood–brain barrier

Abstract

Aβ= : amyloid β; ABC= : ATP-binding cassette; AD= : Alzheimer disease; AQP4= : aquaporin 4; BBB= : blood–brain barrier; CAM= : cell adhesion molecule; cAMP= : cyclic adenosine monophosphate; EAAT= : excitatory amino acid transporters; GTP= : guanosine triphosphate; HIF-1= : hypoxia-inducible factor–1; JAM= : junction-associated molecules; LRP= : low-density lipoprotein receptor-related protein; MMP= : matrix metalloproteinase; MS= : multiple sclerosis; NMO= : neuromyelitis optica; RAGE= : receptor for advanced glycosylation end-product; SLC= : soluble carrier; TGF= : transforming growth factor; TNF= : tumor necrosis factor; VE= : vascular endothelial; VEGF= : vascular endothelial growth factor; ZO= : zonula occludens Neural survival and signaling within the CNS require a highly controlled microenvironment that depends on the normal function of a neurovascular unit, which includes several interacting structures, including capillary endothelial cells, pericytes, astrocytes, and neuronal processes (figure 1). The blood–brain barrier (BBB) is a dynamic component of this unit and is a key interface for molecular exchange between the blood and the brain interstitial fluid. The endothelial cells that form the BBB are characterized by the presence of tight junctions, the polarized expression of membrane transporters and receptors responsible for the active transport of nutrients and efflux of potentially toxic substances, and the presence of enzymes that target neurotransmitters or their precursors. All these cells participate in reciprocal interactions that are critical for local regulation of blood flow, BBB permeability, homeostasis of the neuronal microenvironment, synaptic remodeling, neurogenesis, and angiogenesis. Impaired BBB function contributes to the pathophysiology of a wide range of neurologic disorders, including traumatic, vascular, inflammatory, neoplastic, toxic-metabolic, and degenerative disorders. The pathophysiologic mechanisms include disruption of tight junctions, altered transport of molecules, inflammatory responses, impaired astrocyte function, and brain hypoperfusion. However, the normal BBB may reduce the CNS bioavailability of potentially useful therapeutic agents. Thus, the BBB constitutes an important therapeutic target. The structure and multiple functions of the BBB and their involvement in neurologic disorders have been extensively reviewed.1,–,12 Figure 1 Neurovascular unit and molecular components of the physical blood–brain barrier (BBB) The BBB is an integral part of the neurovascular unit, which includes brain endothelial cells, pericytes, and smooth muscle cells; astrocytes; neuronal terminals; and circulating white blood cells interacting with the vessel wall. All these different cell types express a wide variety of receptors, ion channels, and transporters and their close proximity with each other allows for effective paracrine interactions. The BBB acts as a physical barrier because of the presence of …