Trends in Neurosciences
Volume 38, Issue 10, October 2015, Pages 598-608
Journal home page for Trends in Neurosciences

Review
Special Issue: Neuroimmunology
The Molecular Constituents of the Blood–Brain Barrier

https://doi.org/10.1016/j.tins.2015.08.003Get rights and content

Trends

The BBB comprises CNS endothelial cells that display specialized molecular properties essential for BBB function and integrity.

These molecular BBB properties are not intrinsic to CNS endothelial cells but have to be induced by the environment.

The formation, function, and maintenance of the BBB require functional interaction between CNS endothelial cells and NVUs.

Advances in gene profiling and cell-type purification methods have progressed the identification of the molecular mediators and core cellular pathways involved in BBB function and integrity.

A comprehensive understanding of the key molecules and cellular pathways involved in BBB function would offer novel strategies for CNS therapeutics.

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.

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)

  • E. Posokhova

    GPR124 functions as a WNT7-specific coactivator of canonical β-catenin signaling

    Cell Rep.

    (2015)
  • S.J. Tam

    Death receptors DR6 and TROY regulate brain vascular development

    Dev. Cell

    (2012)
  • Z. Zhao et al.

    Blood–brain barrier: a dual life of MFSD2A?

    Neuron

    (2014)
  • F.T. Yen

    Lipolysis stimulated lipoprotein receptor: a novel molecular link between hyperlipidemia, weight gain, and atherosclerosis in mice

    J. Biol. Chem.

    (2008)
  • E. Martí et al.

    Sonic hedgehog in CNS development: one signal, multiple outputs

    Trends Neurosci.

    (2002)
  • E.Y. Hsiao

    Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders

    Cell

    (2013)
  • P.M. Gross

    The microcirculation of rat circumventricular organs and pituitary gland

    Brain Res. Bull.

    (1987)
  • K. Hatherell

    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

    (2011)
  • Y.J. Yu et al.

    Developing therapeutic antibodies for neurodegenerative disease

    Neurotherapeutics

    (2013)
  • J. Niewoehner

    Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle

    Neuron

    (2014)
  • B.J. Andreone

    Neuronal and vascular interactions

    Annu. Rev. Neurosci.

    (2015)
  • B. Obermeier

    Development, maintenance and disruption of the blood–brain barrier

    Nat. Med.

    (2013)
  • P. Ehrlich

    Das Sauerstoff-Bedürfniss des Organismus. Eine farbenanalytische Studie

    (1885)
  • P. Ehrlich

    Ueber die Beziehungen von chemischer Constitution, Verteilung und pharmakologischer Wirkung

    Gesammelte Arbeiten zur Immunitaetsforschung

    (1904)
  • E.E. Goldmann

    Die äussere und innere Skeretion des gesunden Organismus im Lichte der “vitalen Färbung”

    (1909)
  • A.A. Vein

    Science and fate: Lina Stern (1878-1968), a neurophysiologist and biochemist

    J. Hist. Neurosci.

    (2008)
  • T.S. Reese et al.

    Fine structural localization of a blood–brain barrier to exogenous peroxidase

    J. Cell Biol.

    (1967)
  • M.W. Brightman et al.

    Junctions between intimately apposed cell membranes in the vertebrate brain

    J. Cell Biol.

    (1969)
  • A.L. Betz et al.

    Polarity of the blood–brain barrier: neutral amino acid transport into isolated brain capillaries

    Science

    (1978)
  • R. Daneman et al.

    The blood–brain barrier

    Cold Spring Harb. Perspect. Biol.

    (2015)
  • J.R. Pappenheimer

    Filtration, diffusion and molecular sieving through peripheral capillary membranes. A contribution to the pore theory of capillary permeability

    Am. J. Physiol.

    (1951)
  • W-Y. Liu

    Tight junction in blood–brain barrier: an overview of structure, regulation, and regulator substances

    CNS Neurosci. Ther.

    (2012)
  • S. Tietz et al.

    Brain barriers: crosstalk between complex tight junctions and adherens junctions

    J. Cell Biol.

    (2015)
  • P.L. Tuma et al.

    Transcytosis: crossing cellular barriers

    Physiol. Rev.

    (2003)
  • G. Xiao et al.

    Receptor-mediated endocytosis and brain delivery of therapeutic biologics

    Int. J. Cell Biol.

    (2013)
  • A.H. Schinkel

    Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A

    J. Clin. Invest.

    (1995)
  • I.A. Simpson

    Supply and demand in cerebral energy metabolism: the role of nutrient transporters

    J. Cereb. Blood Flow Metab.

    (2007)
  • R.M. Ransohoff et al.

    The anatomical and cellular basis of immune surveillance in the central nervous system

    Nat. Rev. Immunol.

    (2012)
  • L.L. Muldoon

    Immunologic privilege in the central nervous system and the blood–brain barrier

    J. Cereb. Blood Flow Metab.

    (2013)
  • N. Hagan et al.

    The molecular, cellular, and morphological components of blood–brain barrier development during embryogenesis

    Semin. Cell Dev. Biol.

    (2014)
  • Cited by (274)

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