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Article ; Online: The Role of Sphingolipids and Specialized Pro-Resolving Mediators in Alzheimer's Disease.

de Wit, Nienke M / Mol, Kevin / Rodríguez-Lorenzo, Sabela / de Vries, Helga E / Kooij, Gijs

2021 Volume 11, Page(s) 620348

Abstract: Alzheimer's disease (AD) is the leading cause of dementia worldwide giving rise to devastating forms of cognitive decline, which impacts patients' lives and that of their proxies. Pathologically, AD is characterized by extracellular amyloid deposition, ... ...

Abstract	Alzheimer's disease (AD) is the leading cause of dementia worldwide giving rise to devastating forms of cognitive decline, which impacts patients' lives and that of their proxies. Pathologically, AD is characterized by extracellular amyloid deposition, neurofibrillary tangles and chronic neuroinflammation. To date, there is no cure that prevents progression of AD. In this review, we elaborate on how bioactive lipids, including sphingolipids (SL) and specialized pro-resolving lipid mediators (SPM), affect ongoing neuroinflammatory processes during AD and how we may exploit them for the development of new biomarker panels and/or therapies. In particular, we here describe how SPM and SL metabolism, ranging from ω-3/6 polyunsaturated fatty acids and their metabolites to ceramides and sphingosine-1-phosphate, initiates pro- and anti-inflammatory signaling cascades in the central nervous system (CNS) and what changes occur therein during AD pathology. Finally, we discuss novel therapeutic approaches to resolve chronic neuroinflammation in AD by modulating the SPM and SL pathways.
MeSH term(s)	Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Animals ; Central Nervous System/metabolism ; Ceramides/antagonists & inhibitors ; Ceramides/physiology ; Disease Models, Animal ; Fatty Acids, Omega-3/physiology ; Fatty Acids, Omega-6/physiology ; Fatty Acids, Unsaturated/metabolism ; Forecasting ; Humans ; Inflammation ; Lipoxygenases/metabolism ; Lysophospholipids/physiology ; Mice ; Microglia/pathology ; Models, Biological ; Prostaglandin-Endoperoxide Synthases/metabolism ; Receptors, Pattern Recognition/physiology ; Sphingolipids/physiology ; Sphingosine/analogs & derivatives ; Sphingosine/physiology ; Sphingosine 1 Phosphate Receptor Modulators/therapeutic use
Chemical Substances	Ceramides ; Fatty Acids, Omega-3 ; Fatty Acids, Omega-6 ; Fatty Acids, Unsaturated ; Lysophospholipids ; Receptors, Pattern Recognition ; Sphingolipids ; Sphingosine 1 Phosphate Receptor Modulators ; sphingosine 1-phosphate (26993-30-6) ; Lipoxygenases (EC 1.13.11.-) ; Prostaglandin-Endoperoxide Synthases (EC 1.14.99.1) ; Sphingosine (NGZ37HRE42)
Language	English
Publishing date	2021-01-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.620348
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Breaching Brain Barriers: B Cell Migration in Multiple Sclerosis.

Rodriguez-Mogeda, Carla / Rodríguez-Lorenzo, Sabela / Attia, Jiji / van Horssen, Jack / Witte, Maarten E / de Vries, Helga E

Biomolecules

2022 Volume 12, Issue 6

Abstract: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) known for the manifestation of demyelinated lesions throughout the CNS, leading to neurodegeneration. To date, not all pathological mechanisms that drive disease ... ...

Abstract	Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) known for the manifestation of demyelinated lesions throughout the CNS, leading to neurodegeneration. To date, not all pathological mechanisms that drive disease progression are known, but the clinical benefits of anti-CD20 therapies have put B cells in the spotlight of MS research. Besides their pathological effects in the periphery in MS, B cells gain access to the CNS where they can contribute to disease pathogenesis. Specifically, B cells accumulate in perivascular infiltrates in the brain parenchyma and the subarachnoid spaces of the meninges, but are virtually absent from the choroid plexus. Hence, the possible migration of B cells over the blood-brain-, blood-meningeal-, and blood-cerebrospinal fluid (CSF) barriers appears to be a crucial step to understanding B cell-mediated pathology. To gain more insight into the molecular mechanisms that regulate B cell trafficking into the brain, we here provide a comprehensive overview of the different CNS barriers in health and in MS and how they translate into different routes for B cell migration. In addition, we review the mechanisms of action of diverse therapies that deplete peripheral B cells and/or block B cell migration into the CNS. Importantly, this review shows that studying the different routes of how B cells enter the inflamed CNS should be the next step to understanding this disease.
MeSH term(s)	Blood-Brain Barrier/pathology ; Brain/pathology ; Cell Movement/physiology ; Central Nervous System/pathology ; Humans ; Multiple Sclerosis/pathology
Language	English
Publishing date	2022-06-07
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12060800
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Article ; Online: Single-cell profiling reveals periventricular CD56

Rodríguez-Lorenzo, Sabela / van Olst, Lynn / Rodriguez-Mogeda, Carla / Kamermans, Alwin / van der Pol, Susanne M A / Rodríguez, Ernesto / Kooij, Gijs / de Vries, Helga E

eLife

2022 Volume 11

Abstract: Multiple sclerosis (MS) is a chronic demyelinating disease characterised by immune cell infiltration resulting in lesions that preferentially affect periventricular areas of the brain. Despite research efforts to define the role of various immune cells ... ...

Abstract	Multiple sclerosis (MS) is a chronic demyelinating disease characterised by immune cell infiltration resulting in lesions that preferentially affect periventricular areas of the brain. Despite research efforts to define the role of various immune cells in MS pathogenesis, the focus has been on a few immune cell populations while full-spectrum analysis, encompassing others such as natural killer (NK) cells, has not been performed. Here, we used single-cell mass cytometry (CyTOF) to profile the immune landscape of brain periventricular areas - septum and choroid plexus - and of the circulation from donors with MS, dementia and controls without neurological disease. Using a 37-marker panel, we revealed the infiltration of T cells and antibody-secreting cells in periventricular brain regions and identified a novel NK cell signature specific to MS. CD56
MeSH term(s)	CD56 Antigen/metabolism ; Granzymes ; Humans ; Killer Cells, Natural ; Multiple Sclerosis/metabolism ; Neural Cell Adhesion Molecules/metabolism ; T-Lymphocytes
Chemical Substances	CD56 Antigen ; Neural Cell Adhesion Molecules ; Granzymes (EC 3.4.21.-)
Language	English
Publishing date	2022-05-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.73849
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Article ; Online: Correction to: Inflammation of the choroid plexus in progressive multiple sclerosis: accumulation of granulocytes and T cells.

Rodríguez-Lorenzo, Sabela / Konings, Julia / van der Pol, Susanne / Kamermans, Alwin / Amor, Sandra / van Horssen, Jack / Witte, Maarten E / Kooij, Gijs / de Vries, Helga E

Acta neuropathologica communications

2020 Volume 8, Issue 1, Page(s) 24

Abstract: The original publication of this article [1] contained an incorrect author name. The correct and incorrect information is shown in this correction article. The original article has been updated. ...

Abstract	The original publication of this article [1] contained an incorrect author name. The correct and incorrect information is shown in this correction article. The original article has been updated.
Language	English
Publishing date	2020-02-26
Publishing country	England
Document type	Published Erratum
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-020-00899-5
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Article ; Online: Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis.

Rodríguez-Lorenzo, Sabela / Ferreira Francisco, David Miguel / Vos, Ricardo / van Het Hof, Bert / Rijnsburger, Merel / Schroten, Horst / Ishikawa, Hiroshi / Beaino, Wissam / Bruggmann, Rémy / Kooij, Gijs / de Vries, Helga E

Acta neuropathologica communications

2020 Volume 8, Issue 1, Page(s) 35

Abstract: The choroid plexus (CP) is a key regulator of the central nervous system (CNS) homeostasis through its secretory, immunological and barrier properties. Accumulating evidence suggests that the CP plays a pivotal role in the pathogenesis of multiple ... ...

Abstract	The choroid plexus (CP) is a key regulator of the central nervous system (CNS) homeostasis through its secretory, immunological and barrier properties. Accumulating evidence suggests that the CP plays a pivotal role in the pathogenesis of multiple sclerosis (MS), but the underlying mechanisms remain largely elusive. To get a comprehensive view on the role of the CP in MS, we studied transcriptomic alterations of the human CP in progressive MS and non-neurological disease controls using RNA sequencing. We identified 17 genes with significantly higher expression in progressive MS patients relative to that in controls. Among them is the newly described long non-coding RNA HIF1A-AS3. Next to that, we uncovered disease-affected pathways related to hypoxia, secretion and neuroprotection, while only subtle immunological and no barrier alterations were observed. In an ex vivo CP explant model, a subset of the upregulated genes responded in a similar way to hypoxic conditions. Our results suggest a deregulation of the Hypoxia-Inducible Factor (HIF)-1 pathway in progressive MS CP. Importantly, cerebrospinal fluid levels of the hypoxia-responsive secreted peptide PAI-1 were higher in MS patients with high disability relative to those with low disability. These findings provide for the first time a complete overview of the CP transcriptome in health and disease, and suggest that the CP environment becomes hypoxic in progressive MS patients, highlighting the altered secretory and neuroprotective properties of the CP under neuropathological conditions. Together, these findings provide novel insights to target the CP and promote the secretion of neuroprotective factors into the CNS of progressive MS patients.
MeSH term(s)	Adrenomedullin/cerebrospinal fluid ; Adrenomedullin/genetics ; Adult ; Aged ; Case-Control Studies ; Choroid Plexus/metabolism ; Female ; Gene Expression Profiling ; Gene Ontology ; Glycoproteins/cerebrospinal fluid ; Glycoproteins/genetics ; Humans ; Hypoxia/genetics ; Hypoxia-Inducible Factor 1 ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Intercellular Signaling Peptides and Proteins/cerebrospinal fluid ; Intercellular Signaling Peptides and Proteins/genetics ; Lateral Ventricles ; Male ; Metallothionein/genetics ; Middle Aged ; Multiple Sclerosis, Chronic Progressive/cerebrospinal fluid ; Multiple Sclerosis, Chronic Progressive/genetics ; Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluid ; Multiple Sclerosis, Relapsing-Remitting/genetics ; Neuroprotection/genetics ; Neurosecretion/genetics ; Plasminogen Activator Inhibitor 1/cerebrospinal fluid ; Plasminogen Activator Inhibitor 1/genetics ; RNA, Antisense/genetics ; RNA, Long Noncoding ; RNA-Seq
Chemical Substances	ADM protein, human ; Glycoproteins ; HIF1A protein, human ; Hypoxia-Inducible Factor 1 ; Hypoxia-Inducible Factor 1, alpha Subunit ; Intercellular Signaling Peptides and Proteins ; MT1A protein, human ; Plasminogen Activator Inhibitor 1 ; RNA, Antisense ; RNA, Long Noncoding ; STC2 protein, human ; Adrenomedullin (148498-78-6) ; Metallothionein (9038-94-2)
Language	English
Publishing date	2020-03-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-020-00903-y
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Article ; Online: Inflammation of the choroid plexus in progressive multiple sclerosis: accumulation of granulocytes and T cells.

Rodríguez-Lorenzo, Sabela / Konings, Julia / van der Pol, Susanne / Kamermans, Alwin / Amor, Sandra / van Horssen, Jack / Witte, Maarten E / Kooij, Gijs / de Vries, Helga E

Acta neuropathologica communications

2020 Volume 8, Issue 1, Page(s) 9

Abstract: The choroid plexus (CP) is strategically located between the peripheral blood and the cerebrospinal fluid, and is involved in the regulation of central nervous system (CNS) homeostasis. In multiple sclerosis (MS), demyelination and inflammation occur in ... ...

Abstract	The choroid plexus (CP) is strategically located between the peripheral blood and the cerebrospinal fluid, and is involved in the regulation of central nervous system (CNS) homeostasis. In multiple sclerosis (MS), demyelination and inflammation occur in the CNS. While experimental animal models of MS pointed to the CP as a key route for immune cell invasion of the CNS, little is known about the distribution of immune cells in the human CP during progressive phases of MS. Here, we use immunohistochemistry and confocal microscopy to explore the main immune cell populations in the CP of progressive MS patients and non-neuroinflammatory controls, in terms of abundance and location within the distinct CP compartments. We show for the first time that the CP stromal density of granulocytes and CD8+ T cells is higher in progressive MS patients compared to controls. In line with previous studies, the CP of both controls and progressive MS patients contains relatively high numbers of macrophages and dendritic cells. Moreover, we found virtually no B cells or plasma cells in the CP. MHCII+ antigen-presenting cells were often found in close proximity to T cells, suggesting constitutive CNS immune monitoring functions of the CP. Together, our data highlights the role of the CP in immune homeostasis and indicates the occurrence of mild inflammatory processes in the CP of progressive MS patients. However, our findings suggest that the CP is only marginally involved in immune cell migration into the CNS in chronic MS.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; B-Lymphocytes/immunology ; Choroid Plexus/immunology ; Dendritic Cells/immunology ; Female ; Granulocytes/immunology ; Humans ; Inflammation/complications ; Inflammation/immunology ; Macrophages/immunology ; Male ; Middle Aged ; Multiple Sclerosis, Chronic Progressive/complications ; Multiple Sclerosis, Chronic Progressive/immunology ; T-Lymphocytes/immunology
Language	English
Publishing date	2020-02-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-020-0885-1
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Article ; Online: Advancing brain barriers RNA sequencing: guidelines from experimental design to publication.

Francisco, David M F / Marchetti, Luca / Rodríguez-Lorenzo, Sabela / Frías-Anaya, Eduardo / Figueiredo, Ricardo M / Winter, Peter / Romero, Ignacio Andres / de Vries, Helga E / Engelhardt, Britta / Bruggmann, Rémy

Fluids and barriers of the CNS

2020 Volume 17, Issue 1, Page(s) 51

Abstract: Background: RNA sequencing (RNA-Seq) in its varied forms has become an indispensable tool for analyzing differential gene expression and thus characterization of specific tissues. Aiming to understand the brain barriers genetic signature, RNA seq has ... ...

Abstract	Background: RNA sequencing (RNA-Seq) in its varied forms has become an indispensable tool for analyzing differential gene expression and thus characterization of specific tissues. Aiming to understand the brain barriers genetic signature, RNA seq has also been introduced in brain barriers research. This has led to availability of both, bulk and single-cell RNA-Seq datasets over the last few years. If appropriately performed, the RNA-Seq studies provide powerful datasets that allow for significant deepening of knowledge on the molecular mechanisms that establish the brain barriers. However, RNA-Seq studies comprise complex workflows that require to consider many options and variables before, during and after the proper sequencing process. Main body: In the current manuscript, we build on the interdisciplinary experience of the European PhD Training Network BtRAIN ( https://www.btrain-2020.eu/ ) where bioinformaticians and brain barriers researchers collaborated to analyze and establish RNA-Seq datasets on vertebrate brain barriers. The obstacles BtRAIN has identified in this process have been integrated into the present manuscript. It provides guidelines along the entire workflow of brain barriers RNA-Seq studies starting from the overall experimental design to interpretation of results. Focusing on the vertebrate endothelial blood-brain barrier (BBB) and epithelial blood-cerebrospinal-fluid barrier (BCSFB) of the choroid plexus, we provide a step-by-step description of the workflow, highlighting the decisions to be made at each step of the workflow and explaining the strengths and weaknesses of individual choices made. Finally, we propose recommendations for accurate data interpretation and on the information to be included into a publication to ensure appropriate accessibility of the data and reproducibility of the observations by the scientific community. Conclusion: Next generation transcriptomic profiling of the brain barriers provides a novel resource for understanding the development, function and pathology of these barrier cells, which is essential for understanding CNS homeostasis and disease. Continuous advancement and sophistication of RNA-Seq will require interdisciplinary approaches between brain barrier researchers and bioinformaticians as successfully performed in BtRAIN. The present guidelines are built on the BtRAIN interdisciplinary experience and aim to facilitate collaboration of brain barriers researchers with bioinformaticians to advance RNA-Seq study design in the brain barriers community.
MeSH term(s)	Animals ; Blood-Brain Barrier/metabolism ; Computational Biology ; Databases, Factual ; Gene Expression Profiling ; Guidelines as Topic ; Humans ; Neurovascular Coupling ; Peer Review, Research ; Research Design ; Sequence Analysis, RNA/methods
Language	English
Publishing date	2020-08-18
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2595406-4
ISSN	2045-8118 ; 2045-8118
ISSN (online)	2045-8118
ISSN	2045-8118
DOI	10.1186/s12987-020-00207-2
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Article ; Online: Highly polygenic architecture of antidepressant treatment response: Comparative analysis of SSRI and NRI treatment in an animal model of depression.

Malki, Karim / Tosto, Maria Grazia / Mouriño-Talín, Héctor / Rodríguez-Lorenzo, Sabela / Pain, Oliver / Jumhaboy, Irfan / Liu, Tina / Parpas, Panos / Newman, Stuart / Malykh, Artem / Carboni, Lucia / Uher, Rudolf / McGuffin, Peter / Schalkwyk, Leonard C / Bryson, Kevin / Herbster, Mark

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

2016 Volume 174, Issue 3, Page(s) 235–250

Abstract: Response to antidepressant (AD) treatment may be a more polygenic trait than previously hypothesized, with many genetic variants interacting in yet unclear ways. In this study we used methods that can automatically learn to detect patterns of statistical ...

Abstract	Response to antidepressant (AD) treatment may be a more polygenic trait than previously hypothesized, with many genetic variants interacting in yet unclear ways. In this study we used methods that can automatically learn to detect patterns of statistical regularity from a sparsely distributed signal across hippocampal transcriptome measurements in a large-scale animal pharmacogenomic study to uncover genomic variations associated with AD. The study used four inbred mouse strains of both sexes, two drug treatments, and a control group (escitalopram, nortriptyline, and saline). Multi-class and binary classification using Machine Learning (ML) and regularization algorithms using iterative and univariate feature selection methods, including InfoGain, mRMR, ANOVA, and Chi Square, were used to uncover genomic markers associated with AD response. Relevant genes were selected based on Jaccard distance and carried forward for gene-network analysis. Linear association methods uncovered only one gene associated with drug treatment response. The implementation of ML algorithms, together with feature reduction methods, revealed a set of 204 genes associated with SSRI and 241 genes associated with NRI response. Although only 10% of genes overlapped across the two drugs, network analysis shows that both drugs modulated the CREB pathway, through different molecular mechanisms. Through careful implementation and optimisations, the algorithms detected a weak signal used to predict whether an animal was treated with nortriptyline (77%) or escitalopram (67%) on an independent testing set. The results from this study indicate that the molecular signature of AD treatment may include a much broader range of genomic markers than previously hypothesized, suggesting that response to medication may be as complex as the pathology. The search for biomarkers of antidepressant treatment response could therefore consider a higher number of genetic markers and their interactions. Through predominately different molecular targets and mechanisms of action, the two drugs modulate the same Creb1 pathway which plays a key role in neurotrophic responses and in inflammatory processes. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
MeSH term(s)	Animals ; Antidepressive Agents/therapeutic use ; Citalopram/therapeutic use ; Cyclic AMP Response Element-Binding Protein ; Depression/drug therapy ; Depressive Disorder/drug therapy ; Depressive Disorder/genetics ; Disease Models, Animal ; Female ; Hippocampus ; Male ; Mice ; Multifactorial Inheritance/genetics ; Nortriptyline/therapeutic use ; Pharmacogenetics ; Serotonin Uptake Inhibitors/therapeutic use ; Serotonin and Noradrenaline Reuptake Inhibitors/pharmacology ; Serotonin and Noradrenaline Reuptake Inhibitors/therapeutic use ; Transcriptome/genetics ; Treatment Outcome
Chemical Substances	Antidepressive Agents ; Creb1 protein, mouse ; Cyclic AMP Response Element-Binding Protein ; Serotonin Uptake Inhibitors ; Serotonin and Noradrenaline Reuptake Inhibitors ; Citalopram (0DHU5B8D6V) ; Nortriptyline (BL03SY4LXB)
Language	English
Publishing date	2016-10-01
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	2108616-3
ISSN	1552-485X ; 1552-4841 ; 0148-7299
ISSN (online)	1552-485X
ISSN	1552-4841 ; 0148-7299
DOI	10.1002/ajmg.b.32494
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Article ; Online: The Role of Sphingolipids and Specialized Pro-Resolving Mediators in Alzheimer's Disease.

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Article ; Online: Breaching Brain Barriers: B Cell Migration in Multiple Sclerosis.

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Article ; Online: Single-cell profiling reveals periventricular CD56

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Article ; Online: Correction to: Inflammation of the choroid plexus in progressive multiple sclerosis: accumulation of granulocytes and T cells.

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Article ; Online: Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis.

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Article ; Online: Inflammation of the choroid plexus in progressive multiple sclerosis: accumulation of granulocytes and T cells.

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Article ; Online: Advancing brain barriers RNA sequencing: guidelines from experimental design to publication.

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Article ; Online: Highly polygenic architecture of antidepressant treatment response: Comparative analysis of SSRI and NRI treatment in an animal model of depression.

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