Trends in Neurosciences
ReviewSpecial Issue: NeuroimmunologyThe Molecular Constituents of the Blood–Brain Barrier
Section snippets
History of the BBB
The BBB (see Glossary) partitions the brain from circulating blood and functions to: (i) shield the brain from potential blood-borne toxins; (ii) meet the metabolic demands of the brain; and (iii) regulate the homeostatic environment in the CNS for proper neuronal function [1]. The functional BBB comprises CNS endothelial cells, pericytes, astrocytes, and neurons that collectively form a functional ‘neurovascular unit’ (NVU) (Figure 1) [2].
The BBB was first observed over a century ago.
Molecular Properties of the BBB
CNS endothelial cells are highly polarized with distinct luminal (apical) and abluminal (basolateral) compartments [9]. The polarized nature of CNS endothelial cells is reflected in their four fundamental barrier properties that contribute to BBB function and integrity (Figure 2) [10]. First, circumferential tight junction complexes at the lateral, apical membrane between CNS endothelial cells establish a high-resistance paracellular barrier to small hydrophilic molecules and ions 8, 11. Tight
Identifying Molecular Regulators of BBB Function and Integrity in CNS Endothelial Cells
The four fundamental BBB properties listed above are not intrinsic to CNS endothelial cells but are induced and regulated by the neural environment [27]. Transplantation studies using chick/quail chimeras have demonstrated that nonvascularized brain fragments transplanted into the coelomic cavity were soon vascularized by abdominal vessels that developed BBB characteristics such as exclusion of circulating dye and low number of vesicles [28]. By contrast, nonvascularized embryonic mesoderm
Identifying Inductive Signals that Confer BBB Properties
Recent studies have identified key inductive signals in the CNS microenvironment that confer BBB properties on CNS endothelial cells (Table 2). It is evident that these inductive signals originate from the NVU. As mentioned above, the most well-characterized signal that mediates BBB function is canonical Wnt signaling 29, 30, 31, 33. Neural progenitors in the neuroepithelium secrete Wnt7a/Wnt7b, whereas in the cerebellum Bergmann glia secrete Norrin. These secreted ligands bind to classical
Future Directions of BBB Research
Although the BBB research community has recently made significant strides in identifying novel molecular regulators and inductive signals that mediate BBB function and integrity, the field remains in its infancy, with many fundamental questions waiting to be answered (see Outstanding Questions). Further refinements of cell-type purification techniques and next-generation sequencing technologies will unravel key molecular regulators and core pathways essential for BBB formation and function.
Concluding Remarks
The BBB comprises specialized CNS endothelial cells that regulate CNS homeostasis to ensure proper neuronal function. In this review we have highlighted that improvements in experimental tools have facilitated the recent finding of molecular constituents that mediate BBB function and integrity. These discoveries have greatly expanded our molecular and cellular understanding of this specialized vasculature that has fascinated physiologists for more than a century. Nevertheless, these discoveries
Acknowledgments
The authors are grateful to the colleagues, friends, and laboratory members who contributed to reading and editing this review. This review received funding from an NIH Pioneer Award (1DP1NS092473-01).
Glossary
- Angiogenesis
- the development of new vessels from proliferation of pre-existing endothelial cells.
- Blood–brain barrier (BBB)
- a physiological barrier comprising a thin layer of continuous, non-fenestrated CNS endothelial cells that regulates the brain microenvironment for proper neuronal function.
- Endothelial cells
- mesoderm-derived cells that line the vasculature of the circulatory system.
- Immune privilege
- the introduction of antigens without eliciting an inflammatory adaptive immune response.
References (80)
“Sealing off the CNS”: cellular and molecular regulation of blood–brain barriergenesis
Curr. Opin. Neurobiol.
(2013)- et al.
Tight junctions and the regulation of gene expression
Biochim. Biophys. Acta
(2009) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs
Cell
(1994)- et al.
Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases
Prog. Neurobiol.
(2005) Transporters of the blood–brain and blood–CSF interfaces in development and in the adult
Mol. Aspects Med.
(2013)A call for systematic research on solute carriers
Cell
(2015)- et al.
Capture, crawl, cross: the T cell code to breach the blood–brain barriers
Trends Immunol.
(2012) - et al.
Developing nervous tissue induces formation of blood–brain barrier characteristics in invading endothelial cells: a study using quail–chick transplantation chimeras
Dev. Biol.
(1981) Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity
Cell
(2012)- et al.
Gpr124 controls CNS angiogenesis and blood–brain barrier integrity by promoting ligand-specific canonical wnt signaling
Dev. Cell
(2014)
GPR124 functions as a WNT7-specific coactivator of canonical β-catenin signaling
Cell Rep.
Death receptors DR6 and TROY regulate brain vascular development
Dev. Cell
Blood–brain barrier: a dual life of MFSD2A?
Neuron
Lipolysis stimulated lipoprotein receptor: a novel molecular link between hyperlipidemia, weight gain, and atherosclerosis in mice
J. Biol. Chem.
Sonic hedgehog in CNS development: one signal, multiple outputs
Trends Neurosci.
Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders
Cell
The microcirculation of rat circumventricular organs and pituitary gland
Brain Res. Bull.
Development of a three-dimensional, all-human in vitro model of the blood–brain barrier using mono-, co-, and tri-cultivation Transwell models
J. Neurosci. Methods
Developing therapeutic antibodies for neurodegenerative disease
Neurotherapeutics
Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle
Neuron
Neuronal and vascular interactions
Annu. Rev. Neurosci.
Development, maintenance and disruption of the blood–brain barrier
Nat. Med.
Das Sauerstoff-Bedürfniss des Organismus. Eine farbenanalytische Studie
Ueber die Beziehungen von chemischer Constitution, Verteilung und pharmakologischer Wirkung
Gesammelte Arbeiten zur Immunitaetsforschung
Die äussere und innere Skeretion des gesunden Organismus im Lichte der “vitalen Färbung”
Science and fate: Lina Stern (1878-1968), a neurophysiologist and biochemist
J. Hist. Neurosci.
Fine structural localization of a blood–brain barrier to exogenous peroxidase
J. Cell Biol.
Junctions between intimately apposed cell membranes in the vertebrate brain
J. Cell Biol.
Polarity of the blood–brain barrier: neutral amino acid transport into isolated brain capillaries
Science
The blood–brain barrier
Cold Spring Harb. Perspect. Biol.
Filtration, diffusion and molecular sieving through peripheral capillary membranes. A contribution to the pore theory of capillary permeability
Am. J. Physiol.
Tight junction in blood–brain barrier: an overview of structure, regulation, and regulator substances
CNS Neurosci. Ther.
Brain barriers: crosstalk between complex tight junctions and adherens junctions
J. Cell Biol.
Transcytosis: crossing cellular barriers
Physiol. Rev.
Receptor-mediated endocytosis and brain delivery of therapeutic biologics
Int. J. Cell Biol.
Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A
J. Clin. Invest.
Supply and demand in cerebral energy metabolism: the role of nutrient transporters
J. Cereb. Blood Flow Metab.
The anatomical and cellular basis of immune surveillance in the central nervous system
Nat. Rev. Immunol.
Immunologic privilege in the central nervous system and the blood–brain barrier
J. Cereb. Blood Flow Metab.
The molecular, cellular, and morphological components of blood–brain barrier development during embryogenesis
Semin. Cell Dev. Biol.
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