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1.
PLoS One. 2019 Nov 14;14(11):e0225206. doi: 10.1371/journal.pone.0225206. eCollection 2019.

Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids.

Author information

1
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States of America.
2
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States of America.
3
Departments of Neurosciences and Pharmacology, University of California, San Diego, La Jolla, CA, United States of America.
4
Department of Pharmacology, University of California, San Diego, La Jolla, CA, United States of America.

Abstract

The engineered AAV-PHP.B family of adeno-associated virus efficiently delivers genes throughout the mouse central nervous system. To guide their application across disease models, and to inspire the development of translational gene therapy vectors for targeting neurological diseases in humans, we sought to elucidate the host factors responsible for the CNS tropism of the AAV-PHP.B vectors. Leveraging CNS tropism differences across 13 mouse strains, we systematically determined a set of genetic variants that segregate with the permissivity phenotype, and rapidly identified LY6A as an essential receptor for the AAV-PHP.B vectors. Interfering with LY6A by CRISPR/Cas9-mediated Ly6a disruption or with blocking antibodies reduced transduction of mouse brain endothelial cells by AAV-PHP.eB, while ectopic expression of Ly6a increased AAV-PHP.eB transduction of HEK293T and CHO cells by 30-fold or more. Importantly, we demonstrate that this newly discovered mode of AAV binding and transduction can occur independently of other known AAV receptors. These findings illuminate the previously reported species- and strain-specific tropism characteristics of the AAV-PHP.B vectors and inform ongoing efforts to develop next-generation AAV vehicles for human CNS gene therapy.

Conflict of interest statement

B.D. and K.C. are inventors on patents related to the AAV-PHP.B vectors filed by the California Institute of Technology; a provisional patent application related to this work controlled by the Broad Institute has been filed; B.D. is a consultant for Voyager Therapeutics and a member of the Scientific Advisory Board for Tevard Therapeutics. All other authors declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

2.
Nat Neurosci. 2019 Nov;22(11):1892-1902. doi: 10.1038/s41593-019-0497-x. Epub 2019 Oct 14.

Profiling the mouse brain endothelial transcriptome in health and disease models reveals a core blood-brain barrier dysfunction module.

Author information

1
Departments of Pharmacology and Neurosciences, University of California, San Diego, San Diego, CA, USA.
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
3
Department of Neurosurgery and Neurobiology, Barrow Aneurysm and AVM Research Center, Barrow Neurological Institute, Phoenix, AZ, USA.
4
Departments of Pharmacology and Neurosciences, University of California, San Diego, San Diego, CA, USA. Rdaneman@ucsd.edu.

Abstract

Blood vessels in the CNS form a specialized and critical structure, the blood-brain barrier (BBB). We present a resource to understand the molecular mechanisms that regulate BBB function in health and dysfunction during disease. Using endothelial cell enrichment and RNA sequencing, we analyzed the gene expression of endothelial cells in mice, comparing brain endothelial cells with peripheral endothelial cells. We also assessed the regulation of CNS endothelial gene expression in models of stroke, multiple sclerosis, traumatic brain injury and seizure, each having profound BBB disruption. We found that although each is caused by a distinct trigger, they exhibit strikingly similar endothelial gene expression changes during BBB disruption, comprising a core BBB dysfunction module that shifts the CNS endothelial cells into a peripheral endothelial cell-like state. The identification of a common pathway for BBB dysfunction suggests that targeting therapeutic agents to limit it may be effective across multiple neurological disorders.

PMID:
31611708
PMCID:
PMC6858546
[Available on 2020-04-14]
DOI:
10.1038/s41593-019-0497-x
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3.
Sci Adv. 2019 Mar 13;5(3):eaau7375. doi: 10.1126/sciadv.aau7375. eCollection 2019 Mar.

Human pluripotent stem cell-derived brain pericyte-like cells induce blood-brain barrier properties.

Author information

1
Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, USA.
2
Department of Orthopedics and Rehabilitation, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
3
Departments of Neuroscience and Pharmacology, University of California, San Diego, San Diego, CA, USA.

Abstract

Brain pericytes play important roles in the formation and maintenance of the neurovascular unit (NVU), and their dysfunction has been implicated in central nervous system disorders. While human pluripotent stem cells (hPSCs) have been used to model other NVU cell types, including brain microvascular endothelial cells (BMECs), astrocytes, and neurons, hPSC-derived brain pericyte-like cells have not been integrated into these models. In this study, we generated neural crest stem cells (NCSCs), the embryonic precursor to forebrain pericytes, from hPSCs and subsequently differentiated NCSCs to brain pericyte-like cells. These cells closely resembled primary human brain pericytes and self-assembled with endothelial cells. The brain pericyte-like cells induced blood-brain barrier properties in BMECs, including barrier enhancement and reduced transcytosis. Last, brain pericyte-like cells were incorporated with iPSC-derived BMECs, astrocytes, and neurons to form an isogenic human model that should prove useful for the study of the NVU.

4.
Cell Rep. 2017 Oct 31;21(5):1304-1316. doi: 10.1016/j.celrep.2017.10.026.

Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic Transporters in Endogenous Steroid Partitioning and Behavior.

Author information

1
Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA.
2
Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA; Division of Clinical Pharmacology and Experimental Therapeutics, University of California San Francisco, San Francisco, CA, USA; Department of Anatomy, University of California San Francisco, San Francisco, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
3
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
4
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA, USA; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
5
Division of Biological Science, Graduate School of Science, Nagoya University, Japan.
6
Department of Anatomy, University of California San Francisco, San Francisco, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
7
Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.
8
Department of Anatomy, University of California San Francisco, San Francisco, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA. Electronic address: rdaneman@ucsd.edu.
9
Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA. Electronic address: roland.bainton@ucsf.edu.

Abstract

Central nervous system (CNS) chemical protection depends upon discrete control of small-molecule access by the blood-brain barrier (BBB). Curiously, some drugs cause CNS side-effects despite negligible transit past the BBB. To investigate this phenomenon, we asked whether the highly BBB-enriched drug efflux transporter MDR1 has dual functions in controlling drug and endogenous molecule CNS homeostasis. If this is true, then brain-impermeable drugs could induce behavioral changes by affecting brain levels of endogenous molecules. Using computational, genetic, and pharmacologic approaches across diverse organisms, we demonstrate that BBB-localized efflux transporters are critical for regulating brain levels of endogenous steroids and steroid-regulated behaviors (sleep in Drosophila and anxiety in mice). Furthermore, we show that MDR1-interacting drugs are associated with anxiety-related behaviors in humans. We propose a general mechanism for common behavioral side effects of prescription drugs: pharmacologically challenging BBB efflux transporters disrupts brain levels of endogenous substrates and implicates the BBB in behavioral regulation.

KEYWORDS:

behavior; blood brain barrier; central nervous system; drug side effect mechanisms; drug transporters; endobiotics; steroid hormones; toxicology

PMID:
29091768
PMCID:
PMC5774027
DOI:
10.1016/j.celrep.2017.10.026
[Indexed for MEDLINE]
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5.
Mol Ther. 2017 Jul 5;25(7):1531-1543. doi: 10.1016/j.ymthe.2017.03.037. Epub 2017 Apr 26.

A Basic ApoE-Based Peptide Mediator to Deliver Proteins across the Blood-Brain Barrier: Long-Term Efficacy, Toxicity, and Mechanism.

Author information

1
Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Wenzhou-Kean University, Wenzhou, Zhejiang 32050, China.
2
Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
3
Department of Biostatistics, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
4
Department of Pharmacology, Physiology, and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
5
Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
6
Geriatrics Research Education and Clinical Center, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, University of Washington School of Medicine, Seattle, WA 98108, USA.
7
Departments of Pharmacology and Neuroscience, University of California, San Diego, CA 92093, USA.
8
Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Department of Biochemistry and Molecular Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. Electronic address: sleat@cabm.rutgers.edu.
9
Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Department of Biochemistry and Molecular Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. Electronic address: lobel@cabm.rutgers.edu.

Abstract

We have investigated delivery of protein therapeutics from the bloodstream into the brain using a mouse model of late-infantile neuronal ceroid lipofuscinosis (LINCL), a lysosomal disease due to deficiencies in tripeptidyl peptidase 1 (TPP1). Supraphysiological levels of TPP1 are delivered to the mouse brain by acute intravenous injection when co-administered with K16ApoE, a peptide that in trans mediates passage across the blood-brain barrier (BBB). Chronic treatment of LINCL mice with TPP1 and K16ApoE extended the lifespan from 126 to >294 days, diminished pathology, and slowed locomotor dysfunction. K16ApoE enhanced uptake of a fixable biotin tracer by brain endothelial cells in a dose-dependent manner, suggesting that its mechanism involves stimulation of endocytosis. Pharmacokinetic experiments indicated that K16ApoE functions without disrupting the BBB, with minimal effects on overall clearance or uptake by the liver and kidney. K16ApoE has a narrow therapeutic index, with toxicity manifested as lethargy and/or death in mice. To address this, we evaluated variant peptides but found that efficacy and toxicity are associated, suggesting that desired and adverse effects are mechanistically related. Toxicity currently precludes direct clinical application of peptide-mediated delivery in its present form but it remains a useful approach to proof-of-principle studies for biologic therapies to the brain in animal models.

KEYWORDS:

blood brain barrier; enzyme replacement therapy; intravenous; tripeptidyl peptidase 1

PMID:
28456380
PMCID:
PMC5498811
DOI:
10.1016/j.ymthe.2017.03.037
[Indexed for MEDLINE]
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6.
J Cell Biol. 2015 Mar 16;208(6):703-11. doi: 10.1083/jcb.201410131. Epub 2015 Mar 9.

LSR/angulin-1 is a tricellular tight junction protein involved in blood-brain barrier formation.

Author information

1
Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093 Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093 fsohet@ucsd.edu rdaneman@ucsd.edu.
2
Department of Anatomy, Department of Pediatrics, and Department of Neurology, University of California, San Francisco, San Francisco, CA 94143.
3
Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093 Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093.
4
Unité de Recherche Animal et Fonctionnalités des Produits Animaux (URAFPA), EA3998, Université de Lorraine, 54000 Nancy, France.

Abstract

The blood-brain barrier (BBB) is a term used to describe the unique properties of central nervous system (CNS) blood vessels. One important BBB property is the formation of a paracellular barrier made by tight junctions (TJs) between CNS endothelial cells (ECs). Here, we show that Lipolysis-stimulated lipoprotein receptor (LSR), a component of paracellular junctions at points in which three cell membranes meet, is greatly enriched in CNS ECs compared with ECs in other nonneural tissues. We demonstrate that LSR is specifically expressed at tricellular junctions and that its expression correlates with the onset of BBB formation during embryogenesis. We further demonstrate that the BBB does not seal during embryogenesis in Lsr knockout mice with a leakage to small molecules. Finally, in mouse models in which BBB was disrupted, including an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and a middle cerebral artery occlusion (MCAO) model of stroke, LSR was down-regulated, linking loss of LSR and pathological BBB leakage.

PMID:
25753034
PMCID:
PMC4362448
DOI:
10.1083/jcb.201410131
[Indexed for MEDLINE]
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7.
Cold Spring Harb Perspect Biol. 2015 Jan 5;7(1):a020412. doi: 10.1101/cshperspect.a020412.

The blood-brain barrier.

Author information

1
Departments of Neuroscience and Pharmacology, University of California, San Diego, San Diego, California 92093.
2
Department of Neuroscience, Université de Montréal, Montréal, Quebec H2X 0A9, Canada.

Abstract

Blood vessels are critical to deliver oxygen and nutrients to all of the tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, and alterations of these barrier properties are an important component of pathology and progression of different neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the endothelial cells (ECs) that form the walls of the blood vessels, and these properties are regulated by interactions with different vascular, immune, and neural cells. Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.

PMID:
25561720
PMCID:
PMC4292164
DOI:
10.1101/cshperspect.a020412
[Indexed for MEDLINE]
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8.
PLoS Pathog. 2014 Dec 4;10(12):e1004528. doi: 10.1371/journal.ppat.1004528. eCollection 2014 Dec.

Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier.

Author information

1
Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America.
2
Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America.

Abstract

Cerebral malaria claims the lives of over 600,000 African children every year. To better understand the pathogenesis of this devastating disease, we compared the cellular dynamics in the cortical microvasculature between two infection models, Plasmodium berghei ANKA (PbA) infected CBA/CaJ mice, which develop experimental cerebral malaria (ECM), and P. yoelii 17XL (PyXL) infected mice, which succumb to malarial hyperparasitemia without neurological impairment. Using a combination of intravital imaging and flow cytometry, we show that significantly more CD8(+) T cells, neutrophils, and macrophages are recruited to postcapillary venules during ECM compared to hyperparasitemia. ECM correlated with ICAM-1 upregulation on macrophages, while vascular endothelia upregulated ICAM-1 during ECM and hyperparasitemia. The arrest of large numbers of leukocytes in postcapillary and larger venules caused microrheological alterations that significantly restricted the venous blood flow. Treatment with FTY720, which inhibits vascular leakage, neurological signs, and death from ECM, prevented the recruitment of a subpopulation of CD45(hi) CD8(+) T cells, ICAM-1(+) macrophages, and neutrophils to postcapillary venules. FTY720 had no effect on the ECM-associated expression of the pattern recognition receptor CD14 in postcapillary venules suggesting that endothelial activation is insufficient to cause vascular pathology. Expression of the endothelial tight junction proteins claudin-5, occludin, and ZO-1 in the cerebral cortex and cerebellum of PbA-infected mice with ECM was unaltered compared to FTY720-treated PbA-infected mice or PyXL-infected mice with hyperparasitemia. Thus, blood brain barrier opening does not involve endothelial injury and is likely reversible, consistent with the rapid recovery of many patients with CM. We conclude that the ECM-associated recruitment of large numbers of activated leukocytes, in particular CD8(+) T cells and ICAM(+) macrophages, causes a severe restriction in the venous blood efflux from the brain, which exacerbates the vasogenic edema and increases the intracranial pressure. Thus, death from ECM could potentially occur as a consequence of intracranial hypertension.

PMID:
25474413
PMCID:
PMC4256476
DOI:
10.1371/journal.ppat.1004528
[Indexed for MEDLINE]
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9.
Front Neurosci. 2014 Nov 6;8:355. doi: 10.3389/fnins.2014.00355. eCollection 2014.

Dissecting gene expression at the blood-brain barrier.

Author information

1
Department of Bioinformatics and Computational Biology, Genentech Inc. South San Francisco, CA, USA.
2
Department of Neuroscience, Genentech Inc. South San Francisco, CA, USA.
3
Department of Pharmacology, University of California, San Diego La Jolla, CA, USA.

Abstract

The availability of genome-wide expression data for the blood-brain barrier is an invaluable resource that has recently enabled the discovery of several genes and pathways involved in the development and maintenance of the blood-brain barrier, particularly in rodent models. The broad distribution of published data sets represents a viable starting point for the molecular dissection of the blood-brain barrier and will further direct the discovery of novel mechanisms of blood-brain barrier formation and function. Technical advances in purifying brain endothelial cells, the key cell that forms the critical barrier, have allowed for greater specificity in gene expression comparisons with other central nervous system cell types, and more systematic characterizations of the molecular composition of the blood-brain barrier. Nevertheless, our understanding of how the blood-brain barrier changes during aging and disease is underrepresented. Blood-brain barrier data sets from a wider range of experimental paradigms and species, including invertebrates and primates, would be invaluable for investigating the function and evolution of the blood-brain barrier. Newer technologies in gene expression profiling, such as RNA-sequencing, now allow for finer resolution of transcriptomic changes, including isoform specificity and RNA-editing. As our field continues to utilize more advanced expression profiling in its ongoing efforts to elucidate the blood-brain barrier, including in disease and drug delivery, we will continue to see rapid advances in our understanding of the molecular mediators of barrier biology. We predict that the recently published data sets, combined with forthcoming genomic and proteomic blood-brain barrier data sets, will continue to fuel the molecular genetic revolution of.

KEYWORDS:

blood-brain barrier; brain endothelial cells; expression profiling; genomics; transcriptome

Publication type

Publication type

10.
Nat Med. 2013 Dec;19(12):1584-96. doi: 10.1038/nm.3407. Epub 2013 Dec 5.

Development, maintenance and disruption of the blood-brain barrier.

Author information

1
Neuroinflammation Research Center, Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Abstract

The interface between the blood circulation and the neural tissue features unique characteristics that are encompassed by the term 'blood-brain barrier' (BBB). The main functions of this barrier, namely maintenance of brain homeostasis, regulation of influx and efflux transport, and protection from harm, are determined by its specialized multicellular structure. Every constituent cell type makes an indispensable contribution to the BBB's integrity. But if one member of the BBB fails, and as a result the barrier breaks down, there can be dramatic consequences and neuroinflammation and neurodegeneration can occur. In this Review, we highlight recently gained mechanistic insights into the development and maintenance of the BBB. We then discuss how BBB disruption can cause or contribute to neurological disease. Finally, we examine how this knowledge can be used to explore new possibilities for BBB repair.

PMID:
24309662
PMCID:
PMC4080800
DOI:
10.1038/nm.3407
[Indexed for MEDLINE]
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11.
Fluids Barriers CNS. 2013 Jan 10;10(1):3. doi: 10.1186/2045-8118-10-3.

Genetic mouse models to study blood-brain barrier development and function.

Author information

1
UCSF Department of Anatomy, 513 Parnassus Ave HSW1301, San Francisco, 94117, California, USA. Fabien.sohet@ucsf.edu.

Abstract

The blood-brain barrier (BBB) is a complex physiological structure formed by the blood vessels of the central nervous system (CNS) that tightly regulates the movement of substances between the blood and the neural tissue. Recently, the generation and analysis of different genetic mouse models has allowed for greater understanding of BBB development, how the barrier is regulated during health and its response to disease. Here we discuss: 1) Genetic mouse models that have been used to study the BBB, 2) Available mouse genetic tools that can aid in the study of the BBB, and 3) Potential tools that if generated could greatly aid in our understanding of the BBB.

12.
Ann Neurol. 2012 Nov;72(5):648-72. doi: 10.1002/ana.23648.

The blood-brain barrier in health and disease.

Author information

1
Department of Anatomy, University of California-San Francisco, CA, USA. richard.daneman@ucsf.edu

Abstract

The blood-brain barrier (BBB) is a term used to describe a series of properties possessed by the vasculature of the central nervous system (CNS) that tightly regulate the movement of ions, molecules, and cells between the blood and the CNS. This barrier is crucial to provide the appropriate environment to allow for proper neural function, as well as protect the CNS from injury and disease. In this review, I discuss the cellular and molecular composition of the BBB and how the development and function of the BBB is regulated by interactions with the CNS microenvironment. I further discuss what is known about BBB dysfunction during CNS injury and disease, as well as methodology used to deliver drugs across the BBB to the CNS.

PMID:
23280789
DOI:
10.1002/ana.23648
[Indexed for MEDLINE]
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13.
J Neurosci. 2012 Jul 11;32(28):9588-600. doi: 10.1523/JNEUROSCI.5977-11.2012.

Blood-brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat.

Author information

1
Department of Neurology, University of California San Francisco, San Francisco, California 94143-0633, USA.

Abstract

The immaturity of the CNS at birth greatly affects injury after stroke but the contribution of the blood-brain barrier (BBB) to the differential response to stroke in adults and neonates is poorly understood. We asked whether the structure and function of the BBB is disrupted differently in neonatal and adult rats by transient middle cerebral artery occlusion. In adult rats, albumin leakage into injured regions was markedly increased during 2-24 h reperfusion but leakage remained low in the neonates. Functional assays employing intravascular tracers in the neonates showed that BBB permeability to both large (70 kDa dextran) and small (3 kDa dextran), gadolinium (III)-diethyltriaminepentaacetic acid tracers remained largely undisturbed 24 h after reperfusion. The profoundly different functional integrity of the BBB was associated with the largely nonoverlapping patterns of regulated genes in endothelial cells purified from injured and uninjured adult and neonatal brain at 24 h (endothelial transcriptome, 31,042 total probe sets). Within significantly regulated 1266 probe sets in injured adults and 361 probe sets in neonates, changes in the gene expression of the basal lamina components, adhesion molecules, the tight junction protein occludin, and matrix metalloproteinase-9 were among the key differences. The protein expression of collagen-IV, laminin, claudin-5, occludin, and zonula occludens protein 1 was also better preserved in neonatal rats. Neutrophil infiltration remained low in acutely injured neonates but neutralization of cytokine-induced neutrophil chemoattractant-1 in the systemic circulation enhanced neutrophil infiltration, BBB permeability, and injury. The markedly more integrant BBB in neonatal brain than in adult brain after acute stroke may have major implications for the treatment of neonatal stroke.

PMID:
22787045
PMCID:
PMC3539825
DOI:
10.1523/JNEUROSCI.5977-11.2012
[Indexed for MEDLINE]
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14.
PLoS One. 2010 Oct 29;5(10):e13741. doi: 10.1371/journal.pone.0013741.

The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells.

Author information

1
Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America. richard.daneman@ucsf.edu

Abstract

The blood-brain barrier (BBB) maintains brain homeostasis and limits the entry of toxins and pathogens into the brain. Despite its importance, little is known about the molecular mechanisms regulating the development and function of this crucial barrier. In this study we have developed methods to highly purify and gene profile endothelial cells from different tissues, and by comparing the transcriptional profile of brain endothelial cells with those purified from the liver and lung, we have generated a comprehensive resource of transcripts that are enriched in the BBB forming endothelial cells of the brain. Through this comparison we have identified novel tight junction proteins, transporters, metabolic enzymes, signaling components, and unknown transcripts whose expression is enriched in central nervous system (CNS) endothelial cells. This analysis has identified that RXRalpha signaling cascade is specifically enriched at the BBB, implicating this pathway in regulating this vital barrier. This dataset provides a resource for understanding CNS endothelial cells and their interaction with neural and hematogenous cells.

PMID:
21060791
PMCID:
PMC2966423
DOI:
10.1371/journal.pone.0013741
[Indexed for MEDLINE]
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15.
Nature. 2010 Nov 25;468(7323):562-6. doi: 10.1038/nature09513. Epub 2010 Oct 13.

Pericytes are required for blood-brain barrier integrity during embryogenesis.

Author information

1
UCSF Department of Anatomy, 513 Parnassus Avenue, HSW1301, San Francisco, California 94143-0452, USA. Richard.daneman@ucsf.edu

Abstract

Vascular endothelial cells in the central nervous system (CNS) form a barrier that restricts the movement of molecules and ions between the blood and the brain. This blood-brain barrier (BBB) is crucial to ensure proper neuronal function and protect the CNS from injury and disease. Transplantation studies have demonstrated that the BBB is not intrinsic to the endothelial cells, but is induced by interactions with the neural cells. Owing to the close spatial relationship between astrocytes and endothelial cells, it has been hypothesized that astrocytes induce this critical barrier postnatally, but the timing of BBB formation has been controversial. Here we demonstrate that the barrier is formed during embryogenesis as endothelial cells invade the CNS and pericytes are recruited to the nascent vessels, over a week before astrocyte generation. Analysing mice with null and hypomorphic alleles of Pdgfrb, which have defects in pericyte generation, we demonstrate that pericytes are necessary for the formation of the BBB, and that absolute pericyte coverage determines relative vascular permeability. We demonstrate that pericytes regulate functional aspects of the BBB, including the formation of tight junctions and vesicle trafficking in CNS endothelial cells. Pericytes do not induce BBB-specific gene expression in CNS endothelial cells, but inhibit the expression of molecules that increase vascular permeability and CNS immune cell infiltration. These data indicate that pericyte-endothelial cell interactions are critical to regulate the BBB during development, and disruption of these interactions may lead to BBB dysfunction and neuroinflammation during CNS injury and disease.

Comment in

PMID:
20944625
PMCID:
PMC3241506
DOI:
10.1038/nature09513
[Indexed for MEDLINE]
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16.
Immunity. 2009 Nov 20;31(5):722-35. doi: 10.1016/j.immuni.2009.09.012.

The gut immune barrier and the blood-brain barrier: are they so different?

Author information

1
University of California, San Francisco, Department of Anatomy, San Francisco, CA 94143-0452, USA. richard.daneman@ucsf.edu

Abstract

In order to protect itself from a diverse set of environmental pathogens and toxins, the body has developed a number of barrier mechanisms to limit the entry of potential hazards. Here, we compare two such barriers: the gut immune barrier, which is the primary barrier against pathogens and toxins ingested in food, and the blood-brain barrier, which protects the central nervous system from pathogens and toxins in the blood. Although each barrier provides defense in very different environments, there are many similarities in their mechanisms of action. In both cases, there is a physical barrier formed by a cellular layer that tightly regulates the movement of ions, molecules, and cells between two tissue spaces. These barrier cells interact with different cell types, which dynamically regulate their function, and with a different array of immune cells that survey the physical barrier and provide innate and adaptive immunity.

PMID:
19836264
DOI:
10.1016/j.immuni.2009.09.012
[Indexed for MEDLINE]
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17.
Cell. 2005 Oct 7;123(1):9-12.

The blood-brain barrier--lessons from moody flies.

Author information

1
Department of Neurobiology, Stanford University School of Medicine, CA 94305, USA. rdaneman@stanford.edu

Abstract

Despite the importance of the blood-brain barrier (BBB), little is known about the molecular mechanisms that control its integrity. The identification of moody, a gene required for the formation and maintenance of the Drosophila BBB, provides new insight into how paracellular junctions are formed at the barrier. Meanwhile, moody also has been identified in a screen for fly mutants with altered sensitivity to cocaine, remarkably implicating the BBB in the physiological response to narcotics.

PMID:
16213208
DOI:
10.1016/j.cell.2005.09.017
[Indexed for MEDLINE]
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