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 is comprised of specialized CNS endothelial cells with fundamental molecular properties essential for the function and integrity of the BBB. The restrictive nature of the BBB hinders 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 only occurred recently. This review will highlight recent findings describing the molecular determinants and core cellular pathways that confer BBB properties upon CNS endothelial cells.

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

“…CNS vasculature undergoes angiogenesis and remodeling at early postnatal stages (19,20), alterations of which can affect subsequent BBB properties (2,21). To determine whether S1P 1 regulates the BBB directly or indirectly via vascular developmental defects (2, 21), we deleted endothelial S1pr1 in adult mice (>8 wk) and analyzed them for BBB function 4 wk after gene deletion.…”

“…In addition, paucity of endocytotic vesicles in brain ECs results in low rates of transcytosis. Furthermore, brain ECs allow efficient transport of select molecules, such as glucose and amino acids, into the CNS (2). The capillary endothelium is surrounded by a defined basement membrane, pericytes, and astrocytic end-feet processes, constituting the neurovascular unit (NVU), which is essential for maintaining the homeostasis of the CNS (3).…”

“…The capillary endothelium is surrounded by a defined basement membrane, pericytes, and astrocytic end-feet processes, constituting the neurovascular unit (NVU), which is essential for maintaining the homeostasis of the CNS (3). Disruption of the BBB is associated with various CNS diseases, including multiple sclerosis (MS), Alzheimer's disease (AD), and ischemic stroke (1)(2)(3). Conversely, in the normal state, the BBB hinders pharmacotherapy of CNS diseases by limiting drug delivery (4).…”

“…Sphingosine 1-phosphate (S1P), a pleiotropic lipid mediator, interacts with five G protein-coupled receptors (GPCRs), S1P [1][2][3][4][5] , to regulate cell migration, adhesion, survival, and proliferation (6). Recently, an S1P 1 modulator, FTY720 (fingolimod), was approved as the first-line oral drug for relapsing-remitting MS (7).…”

Astrocytic tight junctions control inflammatory CNS lesion pathogenesis

“…To enter the parenchyma from the vasculature, leukocytes and soluble factors must traverse 2 barriers. Initially, they must cross the blood-brain barrier (BBB), which exists at the level of the microvascular endothelium and is sealed by tight junctions (TJs) composed of claudin 5 (CLDN5) and occludin (7). Beyond the BBB lies the perivascular space (PVS), where leukocytes encounter CNS antigen in the context of major histocompatibility complex (MHC) (8).…”