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Engaging neuroscience to advance translational research in brain barrier biology

Key Points

  • Summary points that barrier scientists and neuroscientists need to collaborate on:

  • The neurovascular unit (NVU; comprising cellular and acellular elements of brain vessels, parenchymal cells and peripheral immune cells) incorporates three main functionalities — blood–brain barrier, neuroimmune axis and regulation of the cerebral blood flow — that are tightly integrated in brain physiology and play a part in the pathogenesis of numerous neurological diseases.

  • Exchange of information, nutrients and molecules between systemic and central compartments is controlled by the myriad of NVU transporters, which become dysfunctional in brain diseases such as epilepsy, brain tumours and Alzheimer's disease.

  • Targeting the intracellular signalling pathways that regulate selective blood–brain barrier transporters can potentially be used to enhance brain drug delivery, protect the brain from xenobiotics and prevent the pathogenesis and/or slow the progression of CNS diseases.

  • Neurogenesis and angiogenesis are co-regulated in embryonic and adult brains and are often controlled by the same classes of mediators. Novel methods for co-ordinated stimulation of both neuronal and vascular regeneration will be essential to develop successful brain repair strategies.

  • Progress in understanding and treating brain disease is contingent upon better understanding of the integral function of the NVU in disease, advancing the means to interrogate molecular and functional aspects of the NVU, and the development of strategies to deliver therapeutics across the blood–brain barrier.

  • New high resolution imaging techniques are providing stubstantial advances in the blood–brain barrier field and have a powerful potential for further progress. In particular, in vivo two-photon imaging studies of interactions of glial cells and blood cells with the blood–brain barrier are required to compose an integrated picture of blood–brain barrier regulation and function.

Abstract

The delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain is restricted by brain barriers, of which the most well known are the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier. Recent studies have shown numerous additional roles of these barriers, including an involvement in neurodevelopment, in the control of cerebral blood flow, and — when barrier integrity is impaired — in the pathology of many common CNS disorders such as Alzheimer's disease, Parkinson's disease and stroke.

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Figure 1: The extended neurovascular unit.
Figure 2: Primary transporters in the neurovascular unit.
Figure 3: Barrier interfaces.
Figure 4: MicroPET images of the head biodistribution of a calcium channel blocker.

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Acknowledgements

The meeting on which this report was based was partially funded by an R13 grant from the US National Institutes of Health (Grant 5 R13 CA086959-10). We would like to thank all of the people who attended the Engaging Neuroscience to Advance Brain Barriers Translational Research meeting (March 19–21, 2009), Gleneden Beach, Oregon, USA. Special thanks to Lester Drewes, Martha O'Donnell, Leslie Muldoon and Aliana Kim who were instrumental in the development of this report.

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Correspondence to Edward A. Neuwelt.

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Supplementary information

Supplementary information S1 (box)

Co-Chairs and Members of the Five Committees (PDF 164 kb)

Supplementary information S2 (box)

“Engaging Neuroscience to Advance Brain Barriers Translational Research” (PDF 171 kb)

Supplementary information S3 (box)

Molecular Physiology of the Brain and Brain Barriers Working Group Report (PDF 6070 kb)

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Glossary

Abluminal

Facing the neural cells or brain.

Basal lamina

A thin, continuous layer of extracellular matrix surrounding the brain endothelial cells and pericytes.

Blood–cerebrospinal fluid (CSF) barrier

The blood–CSF barrier is at the choroid plexus epithelial cells, which are joined together by tight junctions. The capillaries in the choroid plexus differ from those of the blood–brain barrier in that there is free movement of molecules between endothelial cells via fenestrations and intercellular gaps.

Blood–labyrinth barrier

The cochlea is a structure of the inner ear involved in sound transduction and is vascularized by a dense set of capillaries that are essential for delivering the nutrients and ions necessary for producing the fluids (endolymph and perilymph) present in the cochlea. These capillaries are lined with endothelial cells that are joined by tight junctions and physiologically form the blood–labyrinth barrier that is essential for sensitive auditory function.

Blood–nerve barrier

The endothelial lining of blood vessels in peripheral nerves is formed by continuous, non-fenestrated endothelia in which individual cells are linked by tight junctions, rendering them impermeable to intravascular macromolecules. This blood–nerve barrier, and a similar mechanism in the innermost perineurial sheath, isolate the endoneurial interstitium, in much the same way as the blood–brain barrier. Other factors, such as the absence of lymphatics, are also analogous to the central nervous system.

Blood–retinal barrier

The blood–retinal barrier has two components: the retinal vascular endothelium and the retinal pigment epithelium. The retinal vascular endothelium is non-fenestrated and has anatomical properties similar to those of cerebral vascular endothelium. The retinal pigment epithelium consists of a layer of epithelial cells, joined by tight junctions, that forms a barrier between the neuroretina and the choroid.

Ependyma

A thin cellular layer lining the ventricular system of the brain. The cells of the ependyma are called ependymal cells and are a type of glia. They are linked by gap junctions, which do not provide an impediment to diffusion of molecules, even against large proteins between cerebrospinal fluid and brain interstitial fluid.

Luminal

Facing the capillary lumen.

Neuro–angiogenic coupling

The coupling of the development of neurons (neurogenesis) with new blood vessel formation (angiogenesis and vasculogenesis).

Neuroependyma

(Also known as neuroepithelium or ventricular zone.) A deep pseudostratified layer of cells lining the embryonic ventricular system that proliferate into radial glial cells and neurons in the embryo, and into glial cells later in development. The cells of the neuroependyma are linked by strap junctions, which limit intercellular movement of molecules — particularly proteins — from cerebrospinal fluid to brain interstitial space in the embryo. By adulthood these cells have transformed to the layer of thin generally non-dividing ependymal cells lining the ventricular system of the mature brain.

Neuro–haemodynamic coupling

The coupling of neuronal firing and synaptic activity with haemodynamic changes (for example, blood volume and blood flow).

Neuro–metabolic coupling

The coupling of neural activity, an energy consuming process, with the energy producing metabolic processes to maintain cellular homeostasis.

Neuro–trophic coupling

The coupling of neuronal production of activity-dependent signals such as growth factors (for example, brain-derived neurotrophic factor (BDNF)) with control of neurogenesis.

Paracellular

Paracellular is used here to refer to the transfer of substances between cells of an endothelium or epithelium. It is in contrast to 'transcellular transport', in which the substances are transported through the cell.

Tripartite synapse

A tripartite (three-part) synapse consists of a presynapse, a postsynapse and a glial cell functioning as a single unit.

Xenobiotic-sensing nuclear receptor

A xenobiotic-activated transcription factor that controls the expression of proteins involved in xenobiotic metabolism and efflux transport.

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Neuwelt, E., Bauer, B., Fahlke, C. et al. Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci 12, 169–182 (2011). https://doi.org/10.1038/nrn2995

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