Publications by authors named "Markus Schwaninger"

143 Publications

Succinate Mediates Tumorigenic Effects Succinate Receptor 1: Potential for New Targeted Treatment Strategies in Succinate Dehydrogenase Deficient Paragangliomas.

Front Endocrinol (Lausanne) 2021 12;12:589451. Epub 2021 Mar 12.

Neuroendocrine Oncology and Metabolism, Medical Department I, Center of Brain, Behavior, and Metabolism, University Medical Center Schleswig-Holstein Lübeck, Lübeck, Germany.

Paragangliomas and pheochromocytomas (PPGLs) are chromaffin tumors associated with severe catecholamine-induced morbidities. Surgical removal is often curative. However, complete resection may not be an option for patients with succinate dehydrogenase subunit A-D () mutations. mutations are associated with a high risk for multiple recurrent, and metastatic PPGLs. Treatment options in these cases are limited and prognosis is dismal once metastases are present. Identification of new therapeutic targets and candidate drugs is thus urgently needed. Previously, we showed elevated expression of succinate receptor 1 () in PPGLs and head and neck paragangliomas. Its ligand succinate has been reported to accumulate due to mutations. We thus hypothesize that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of mutation-derived PPGLs. We confirmed elevated SUCNR1 expression in PPGLs and after knockout in progenitor cells derived from a human pheochromocytoma (hPheo1). Succinate significantly increased viability of -transfected PC12 and ERK pathway signaling compared to control cells. Candidate inhibitors successfully reversed proliferative effects of succinate. Our data reveal an unrecognized oncometabolic function of succinate in PPGLs, providing a growth advantage .
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http://dx.doi.org/10.3389/fendo.2021.589451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994772PMC
March 2021

Sirt3 in POMC neurons controls energy balance in a sex- and diet-dependent manner.

Redox Biol 2021 Mar 13;41:101945. Epub 2021 Mar 13.

Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain; Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain. Electronic address:

Sirtuin 3 (SIRT3) is one of the seven mammalian sirtuin homologs of the yeast Sir2 gene that has emerged as an important player in the regulation of energy metabolism in peripheral tissues. However, its role in the hypothalamus has not been explored. Herein, we show that the genetic inhibition of SIRT3 in the hypothalamic arcuate nucleus (ARC) induced a negative energy balance and improvement of several metabolic parameters. These effects are specific for POMC neurons, because ablation of SIRT3 in POMC, but not in AgRP neurons, decreased body weight and adiposity, increased energy expenditure and brown adipose tissue (BAT) activity, and induced browning in white adipose tissue (WAT). Notably, the depletion of SIRT3 in POMC neurons caused these effects in male mice fed a chow diet but failed to affect energy balance in males fed a high fat diet and females under both type of diets. Overall, we provide the first evidence pointing for a key role of SIRT3 in POMC neurons in the regulation of energy balance.
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http://dx.doi.org/10.1016/j.redox.2021.101945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005845PMC
March 2021

Telmisartan prevents high-fat diet-induced neurovascular impairments and reduces anxiety-like behavior.

J Cereb Blood Flow Metab 2021 Mar 17:271678X211003497. Epub 2021 Mar 17.

Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.

Angiotensin II receptor blockers (telmisartan) prevent rodents from diet-induced obesity and improve their metabolic status. Hyperglycemia and obesity are associated with reduced cerebral blood flow and neurovascular uncoupling which may lead to behavioral deficits. We wanted to know whether a treatment with telmisartan prevents these changes in obesity.We put young mice on high-fat diet and simultaneously treated them with telmisartan. At the end of treatment, we performed laser speckle imaging and magnetic resonance imaging to assess the effect on neurovascular coupling and cerebral blood flow. Different behavioral tests were used to investigate cognitive function.Mice developed diet-induced obesity and after 16, not 8 weeks of high-fat diet, however, the response to whisker pad stimulation was about 30% lower in obese compared to lean mice. Simultaneous telmisartan treatment increased the response again by 10% compared to obese mice. Moreover, telmisartan treatment normalized high-fat diet-induced reduction of cerebral blood flow and prevented a diet-induced anxiety-like behavior. In addition to that, telmisartan affects cellular senescence and string vessel formation in obesity.We conclude, that telmisartan protects against neurovascular unit impairments in a diet-induced obesity setting and may play a role in preventing obesity related cognitive deficits in Alzheimer's disease.
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http://dx.doi.org/10.1177/0271678X211003497DOI Listing
March 2021

Do dimethyl fumarate and nicotinic acid elicit common, potentially HCA -mediated adverse reactions? A combined epidemiological-experimental approach.

Br J Clin Pharmacol 2021 Feb 19. Epub 2021 Feb 19.

Research Department, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.

Aim: Dimethyl fumarate and nicotinic acid activate the hydroxy-carboxylic acid receptor 2 (HCA ) and induce flushing. It is not known whether HCA mediates other adverse drug reactions (ADRs) to these two substances. This study aims to compare ADRs associated with dimethyl fumarate and nicotinic acid, and to discuss whether they are HCA -mediated.

Methods: We identified spontaneous reports of suspected ADRs to dimethyl fumarate and nicotinic acid in the European Adverse Drug Reaction Database (EudraVigilance). These reports were analysed at different hierarchical levels of the Medical Dictionary for Regulatory Activities (MedDRA). In addition, we screened murine organs for HCA expression.

Results: Similarities in the ADR profile of dimethyl fumarate and nicotinic acid included "gastrointestinal signs and symptoms" (odds ratio [OR] 0.8 [0.6-1.1]), "hepatobiliary investigations" (OR 1.3 [0.7-2.5]) and "anxiety disorders and symptoms" (OR 0.9 [0.3-2.2]) in High Level Group Terms; "diarrhoea (excluding infective)" (OR 1.2 [0.7-1.8]) and "liver function analyses" (OR 1.3 [0.7-2.6]) in High Level Terms; and "diarrhoea" (OR 1.2 [0.7-2.0]) and "vomiting" (OR 0.9 [0.4-1.7]) in Preferred Terms. In analogy, HCA was expressed in the gastrointestinal tract, liver and central nervous system (CNS) of murine organs. A discrepant ADR profile was seen for "lymphopenia" (n = 777) at the preferred term level (only reported for dimethyl fumarate) and "blood glucose increased" (more often reported for nicotinic acid; OR 0.1 [0.0-0.5]).

Conclusion: The gastrointestinal ADRs common to both substances may be mediated by HCA . Other ADRs not common to both substances are compound or indication-specific reactions and likely do not involve HCA .
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http://dx.doi.org/10.1111/bcp.14787DOI Listing
February 2021

Parvocellular Oxytocin Neurons and Autism Spectrum Disorders.

Trends Endocrinol Metab 2021 Apr 2;32(4):195-197. Epub 2021 Feb 2.

University of Luebeck, Institute for Experimental and Clinical Pharmacology and Toxicology, Ratzeburger Allee 160, 23562 Luebeck, Germany. Electronic address:

The underlying mechanism of oxytocin (OT) neurons in the development of social interaction remains unclear. In a recent study, Lewis et al. characterized OT neuronal subtypes and provided evidence that expression of the autism spectrum disorder (ASD) gene Fmr1 in parvocellular OT neurons is essential for peer-peer but not filial social interactions.
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http://dx.doi.org/10.1016/j.tem.2021.01.004DOI Listing
April 2021

Absence of Both Thyroid Hormone Transporters MCT8 and OATP1C1 Impairs Neural Stem Cell Fate in the Adult Mouse Subventricular Zone.

Stem Cell Reports 2021 Feb 14;16(2):337-353. Epub 2021 Jan 14.

UMR 7221 Phyma, CNRS/Muséum National d'Histoire Naturelle, 75005 Paris, France. Electronic address:

Adult neural stem cell (NSC) generation in vertebrate brains requires thyroid hormones (THs). How THs enter the NSC population is unknown, although TH availability determines proliferation and neuronal versus glial progenitor determination in murine subventricular zone (SVZ) NSCs. Mice display neurological signs of the severely disabling human disease, Allan-Herndon-Dudley syndrome, if they lack both MCT8 and OATP1C1 transporters, or MCT8 and deiodinase type 2. We analyzed the distribution of MCT8 and OATP1C1 in adult mouse SVZ. Both are strongly expressed in NSCs and at a lower level in neuronal cell precursors but not in oligodendrocyte progenitors. Next, we analyzed Mct8/Oatp1c1 double-knockout mice, where brain uptake of THs is strongly reduced. NSC proliferation and determination to neuronal fates were severely affected, but not SVZ-oligodendroglial progenitor generation. This work highlights how tight control of TH availability determines NSC function and glial-neuron cell-fate choice in adult brains.
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http://dx.doi.org/10.1016/j.stemcr.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878696PMC
February 2021

Neuroprotective epi-drugs quench the inflammatory response and microglial/macrophage activation in a mouse model of permanent brain ischemia.

J Neuroinflammation 2020 Nov 27;17(1):361. Epub 2020 Nov 27.

Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.

Background: Activation of NF-kappaB RelA deacetylated at the lysine residues, except the lysine 310, drives pro-apoptotic transcription in noxious brain ischemia. We showed that the sinergistic combination of the histone deacetilase inhibitor MS-275 with the sirtuin 1 activator resveratrol, at very low doses, restores normal RelA acetylation and elicit neuroprotection in mice subjected to transient middle cerebral artery occlusion (tMCAO) and primary cortical neurons exposed to oxygen-glucose-deprivation (OGD). The present study aims at corroborating the neuroprotective potential of the epigenetic treatment in a model of permanent brain ischemia and investigate its effect on post-ischemic inflammation and microglia activation.

Methods: Male mice subjected to permanent occlusion of the distal MCAO (pMCAO) were treated with vehicle or MS-275 (20 μg/kg) and resveratrol (680 μg/kg) i.p. immediately after the ischemia. Microglia-containing mixed glial cultures were prepared from the brain of 1-3-day-old mice. Primary cortical neurons were prepared from 15-day-old embryonic mice.

Results: MS-275 and resveratrol in combination, but not individually, reduced infarct volume and neurological deficits evaluated 48 h after the pMCAO. At 24 h, the treatment inhibited the RelA binding to Nos2 promoter, reduced the elevated expression of Nos2, Il6, Il1b, Mrc1 and Ym1 and the leukocytes infiltration in the ischemic area. The effect was nonpermanent. The treatment did not limit the sustained leukocyte infiltration or Nos2 and Il1b transcription observed at 7 days. Though, it induced alternative activation markers of microglia/macrophages, Arg1, Ym1 and Fcgr2b that could be added to Mrc1, Tgfb1 and Trem2 spontaneously increased at 7 days after ischemia. At 24 hours the drug treatment quenched the microglia/macrophages activation in the ischemic cortical sections, as shown by the recovered ramified morphology and lowered iNOS or CD68 immunoreactivity in Iba1-positive cells. Both microglia and astrocytes in mixed glial cultures, but not pure astrocytes, displayed signs of activation and iNOS-immunoreactivity when treated with a conditioned medium (NCM) from OGD-exposed cortical neurons. The epigenetic drugs limited the OGD-NCM-mediated activation.

Conclusions: Our findings indicate that single treatment with MS-275 and resveratrol can reduce stroke-mediated brain injury and inflammation observed 2 days after the pMCAO and put the rational to test repeated administration of the drugs. The anti-inflammatory property of MS-275 and resveratrol combination can be ascribed to both primary direct inhibition of microglia/macrophage activation and secondary glial/macrophages inhibition mediated by neuroprotection.
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http://dx.doi.org/10.1186/s12974-020-02028-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694916PMC
November 2020

Obese patients with NASH have increased hepatic expression of SARS-CoV-2 critical entry points.

J Hepatol 2021 02 20;74(2):469-471. Epub 2020 Oct 20.

Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Spain; Galician Agency of Innovation (GAIN), Santiago de Compostela, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574841PMC
February 2021

Endogenous THBD (Thrombomodulin) Mediates Angiogenesis in the Ischemic Brain-Brief Report.

Arterioscler Thromb Vasc Biol 2020 12 8;40(12):2837-2844. Epub 2020 Oct 8.

Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Germany (J.W., D.S., J.C.A., M.A.K., I.S., B.L., S.K., M.S.).

Objective: THBD (thrombomodulin) is part of the anticoagulant protein C-system that acts at the endothelium and is involved in anti-inflammatory and barrier-stabilizing processes. A recombinant soluble form of THBD was shown to have protective effects in different organs, but how the endogenous THBD is regulated during ischemia, particularly in the brain is not known to date. The aim of this study was to investigate the role of THBD, especially in brain endothelial cells, during ischemic stroke. Approach and Results: To induce ischemic brain damage, we occluded the middle cerebral artery of mice. We found an increased endothelial expression of in the peri-infarct area, whereas in the core of the ischemic tissue expression was decreased compared with the contralateral side. We generated a novel Cre/loxP-based mouse line that allows for the inducible deletion of specifically in brain endothelial cells, which worsened stroke outcome 48 hours after middle cerebral artery occlusion. Unexpectedly, we found no signs of increased coagulation, thrombosis, or inflammation in the brain but decreased vessel diameters and impaired angiogenesis in the peri-infarct area that led to a reduced overall vessel length 1 week after stroke induction.

Conclusions: Endogenous THBD acts as a protective factor in the brain during ischemic stroke and enhances vessel diameter and proliferation. These previously unknown properties of THBD could offer new opportunities to affect vessel function after ischemia and thereby improve stroke outcome.
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http://dx.doi.org/10.1161/ATVBAHA.120.315061DOI Listing
December 2020

Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood-brain barrier.

Acta Neuropathol 2020 10 11;140(4):549-567. Epub 2020 Jul 11.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

The proinflammatory cytokine interleukin 1 (IL-1) is crucially involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Herein, we studied the role of IL-1 signaling in blood-brain barrier (BBB) endothelial cells (ECs), astrocytes and microglia for EAE development, using mice with the conditional deletion of its signaling receptor IL-1R1. We found that IL-1 signaling in microglia and astrocytes is redundant for the development of EAE, whereas the IL-1R1 deletion in BBB-ECs markedly ameliorated disease severity. IL-1 signaling in BBB-ECs upregulated the expression of the adhesion molecules Vcam-1, Icam-1 and the chemokine receptor Darc, all of which have been previously shown to promote CNS-specific inflammation. In contrast, IL-1R1 signaling suppressed the expression of the stress-responsive heme catabolizing enzyme heme oxygenase-1 (HO-1) in BBB-ECs, promoting disease progression via a mechanism associated with deregulated expression of the IL-1-responsive genes Vcam1, Icam1 and Ackr1 (Darc). Mechanistically, our data emphasize a functional crosstalk of BBB-EC IL-1 signaling and HO-1, controlling the transcription of downstream proinflammatory genes promoting the pathogenesis of autoimmune neuroinflammation.
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http://dx.doi.org/10.1007/s00401-020-02187-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498485PMC
October 2020

Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of versican.

J Exp Med 2020 10;217(10)

Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA.

Cerebral cavernous malformations (CCMs) form following loss of the CCM protein complex in brain endothelial cells due to increased endothelial MEKK3 signaling and KLF2/4 transcription factor expression, but the downstream events that drive lesion formation remain undefined. Recent studies have revealed that CCM lesions expand by incorporating neighboring wild-type endothelial cells, indicative of a cell nonautonomous mechanism. Here we find that endothelial loss of ADAMTS5 reduced CCM formation in the neonatal mouse model. Conversely, endothelial gain of ADAMTS5 conferred early lesion genesis in the absence of increased KLF2/4 expression and synergized with KRIT1 loss of function to create large malformations. Lowering versican expression reduced CCM burden, indicating that versican is the relevant ADAMTS5 substrate and that lesion formation requires proteolysis but not loss of this extracellular matrix protein. These findings identify endothelial secretion of ADAMTS5 and cleavage of versican as downstream mechanisms of CCM pathogenesis and provide a basis for the participation of wild-type endothelial cells in lesion formation.
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http://dx.doi.org/10.1084/jem.20200140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537394PMC
October 2020

NF-κB signaling in tanycytes mediates inflammation-induced anorexia.

Mol Metab 2020 09 21;39:101022. Epub 2020 May 21.

Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, 23562, Lübeck, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany. Electronic address:

Objectives: Infections, cancer, and systemic inflammation elicit anorexia. Despite the medical significance of this phenomenon, the question of how peripheral inflammatory mediators affect the central regulation of food intake is incompletely understood. Therefore, we have investigated the sickness behavior induced by the prototypical inflammatory mediator IL-1β.

Methods: IL-1β was injected intravenously. To interfere with IL-1β signaling, we deleted the essential modulator of NF-κB signaling (Nemo) in astrocytes and tanycytes.

Results: Systemic IL-1β increased the activity of the transcription factor NF-κB in tanycytes of the mediobasal hypothalamus (MBH). By activating NF-κB signaling, IL-1β induced the expression of cyclooxygenase-2 (Cox-2) and stimulated the release of the anorexigenic prostaglandin E (PGE) from tanycytes. When we deleted Nemo in astrocytes and tanycytes, the IL-1β-induced anorexia was alleviated whereas the fever response and lethargy response were unchanged. Similar results were obtained after the selective deletion of Nemo exclusively in tanycytes.

Conclusions: Tanycytes form the brain barrier that mediates the anorexic effect of systemic inflammation in the hypothalamus.
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http://dx.doi.org/10.1016/j.molmet.2020.101022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292913PMC
September 2020

MCH Neurons Regulate Permeability of the Median Eminence Barrier.

Neuron 2020 07 13;107(2):306-319.e9. Epub 2020 May 13.

Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Str. 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Str. 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany; National Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany. Electronic address:

Melanin-concentrating hormone (MCH)-expressing neurons are key regulators of energy and glucose homeostasis. Here, we demonstrate that they provide dense projections to the median eminence (ME) in close proximity to tanycytes and fenestrated vessels. Chemogenetic activation of MCH neurons as well as optogenetic stimulation of their projections in the ME enhance permeability of the ME by increasing fenestrated vascular loops and enhance leptin action in the arcuate nucleus of the hypothalamus (ARC). Unbiased phosphoRiboTrap-based assessment of cell activation upon chemogenetic MCH neuron activation reveals MCH-neuron-dependent regulation of endothelial cells. MCH neurons express the vascular endothelial growth factor A (VEGFA), and blocking VEGF-R signaling attenuates the leptin-sensitizing effect of MCH neuron activation. Our experiments reveal that MCH neurons directly regulate permeability of the ME barrier, linking the activity of energy state and sleep regulatory neurons to the regulation of hormone accessibility to the ARC.
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http://dx.doi.org/10.1016/j.neuron.2020.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383232PMC
July 2020

Nesfatin-1 decreases the motivational and rewarding value of food.

Neuropsychopharmacology 2020 09 30;45(10):1645-1655. Epub 2020 Apr 30.

Department of Internal Medicine I, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.

Homeostatic and hedonic pathways distinctly interact to control food intake. Dysregulations of circuitries controlling hedonic feeding may disrupt homeostatic mechanisms and lead to eating disorders. The anorexigenic peptides nucleobindin-2 (NUCB2)/nesfatin-1 may be involved in the interaction of these pathways. The endogenous levels of this peptide are regulated by the feeding state, with reduced levels following fasting and normalized by refeeding. The fasting state is associated with biochemical and behavioral adaptations ultimately leading to enhanced sensitization of reward circuitries towards food reward. Although NUCB2/nesfatin-1 is expressed in reward-related brain areas, its role in regulating motivation and preference for nutrients has not yet been investigated. We here report that both dopamine and GABA neurons express NUCB2/nesfatin-1 in the VTA. Ex vivo electrophysiological recordings show that nesfatin-1 hyperpolarizes dopamine, but not GABA, neurons of the VTA by inducing an outward potassium current. In vivo, central administration of nesfatin-1 reduces motivation for food reward in a high-effort condition, sucrose intake and preference. We next adopted a 2-bottle choice procedure, whereby the reward value of sucrose was compared with that of a reference stimulus (sucralose + optogenetic stimulation of VTA dopamine neurons) and found that nesfatin-1 fully abolishes the fasting-induced increase in the reward value of sucrose. These findings indicate that nesfatin-1 reduces energy intake by negatively modulating dopaminergic neuron activity and, in turn, hedonic aspects of food intake. Since nesfatin-1´s actions are preserved in conditions of leptin resistance, the present findings render the NUCB2/nesfatin-1 system an appealing target for the development of novel therapeutical treatments towards obesity.
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http://dx.doi.org/10.1038/s41386-020-0682-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419560PMC
September 2020

MS and LC libraries for untargeted metabolomics: Enhancing method development and identification confidence.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 May 4;1145:122105. Epub 2020 Apr 4.

Bioanalytic Core Facility, Center for Brain Behavior and Metabolism, University of Lübeck, Lübeck, Germany. Electronic address:

As part of the "omics" technologies in the life sciences, metabolomics is becoming increasingly important. In untargeted metabolomics, unambiguous metabolite identification and the inevitable coverage bias that comes with the selection of analytical conditions present major challenges. Reliable compound annotation is essential for translating metabolomics data into meaningful biological information. Here, we developed a fast and transferable method for generating in-house MS libraries to improve metabolite identification. Using the new method we established an in-house MS library that includes over 4,000 fragmentation spectra of 506 standard compounds for 6 different normalized collision energies (NCEs). Additionally, we generated a comprehensive liquid chromatography (LC) library by testing 57 different LC-MS conditions for 294 compounds. We used the library information to develop an untargeted metabolomics screen with maximum coverage of the metabolome that was successfully tested in a study of 360 human serum samples. The current work demonstrates a workflow for LC-MS/MS-based metabolomics, with enhanced metabolite identification confidence and the possibility to select suitable analysis conditions according to the specific research interest.
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http://dx.doi.org/10.1016/j.jchromb.2020.122105DOI Listing
May 2020

Cerebral angiogenesis ameliorates pathological disorders in -deficient mice with small-vessel disease.

J Cereb Blood Flow Metab 2021 Feb 9;41(2):219-235. Epub 2020 Mar 9.

Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.

Cerebral small-vessel diseases (SVDs) often follow a progressive course. Little is known about the function of angiogenesis, which potentially induces regression of SVDs. Here, we investigated angiogenesis in a mouse model of incontinentia pigmenti (IP), a genetic disease comprising features of SVD. IP is caused by inactivating mutations of , the essential component of NF-κB signaling. When deleting in the majority of brain endothelial cells ( mice), the transcriptional profile of vessels indicated cell proliferation. Brain endothelial cells expressed Ki67 and showed signs of DNA synthesis. In addition to cell proliferation, we observed sprouting and intussusceptive angiogenesis in mice. Angiogenesis occurred in all segments of the vasculature and in proximity to vessel rarefaction and tissue hypoxia. Apparently, NEMO was required for productive angiogenesis because endothelial cells that had escaped inactivation showed a higher proliferation rate than -deficient cells. Therefore, newborn endothelial cells were particularly vulnerable to ongoing recombination. When we interfered with productive angiogenesis by inducing ongoing ablation of , mice did not recover from IP manifestations but rather showed severe functional deficits. In summary, the data demonstrate that angiogenesis is present in this model of SVD and suggest that it may counterbalance the loss of vessels.
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http://dx.doi.org/10.1177/0271678X20910522DOI Listing
February 2021

Dll4 Suppresses Transcytosis for Arterial Blood-Retinal Barrier Homeostasis.

Circ Res 2020 03 12;126(6):767-783. Epub 2020 Feb 12.

From the Graduate School of Medical Science and Engineering (J.M.Y., C.S.P., S.H.K., T.W.N., J.-H.K., S.P., P.K., Y.S.J., I.K.), Korea Advanced Institute of Science and Technology (KAIST), Daejeon.

Rationale: Central nervous system has low vascular permeability by organizing tight junction (TJ) and limiting endothelial transcytosis. While TJ has long been considered to be responsible for vascular barrier in central nervous system, suppressed transcytosis in endothelial cells is now emerging as a complementary mechanism. Whether transcytosis regulation is independent of TJ and its dysregulation dominantly causes diseases associated with edema remain elusive. Dll4 signaling is important for various vascular contexts, but its role in the maintenance of vascular barrier in central nervous system remains unknown.

Objective: To find a TJ-independent regulatory mechanism selective for transcytosis and identify its dysregulation as a cause of pathological leakage.

Methods And Results: We studied transcytosis in the adult mouse retina with low vascular permeability and employed a hypertension-induced retinal edema model for its pathological implication. Both antibody-based and genetic inactivation of Dll4 or Notch1 induce hyperpermeability by increasing transcytosis without junctional destabilization in arterial endothelial cells, leading to nonhemorrhagic leakage predominantly in the superficial retinal layer. Endothelial deletion represses Dll4 in retinal arteries, phenocopying Dll4 blocking-driven vascular leakage. Ang II (angiotensin II)-induced hypertension represses arterial Sox17 and Dll4, followed by transcytosis-driven retinal edema, which is rescued by a gain of Notch activity. Transcriptomic profiling of retinal endothelial cells suggests that Dll4 blocking activates SREBP1 (sterol regulatory element-binding protein 1)-mediated lipogenic transcription and enriches gene sets favorable for caveolae formation. Profiling also predicts the activation of VEGF (vascular endothelial growth factor) signaling by Dll4 blockade. Inhibition of SREBP1 or VEGF-VEGFR2 (VEGF receptor 2) signaling attenuates both Dll4 blockade-driven and hypertension-induced retinal leakage.

Conclusions: In the retina, Sox17-Dll4-SREBP1 signaling axis controls transcytosis independently of TJ in superficial arteries among heterogeneous regulations for the whole vessels. Uncontrolled transcytosis via dysregulated Dll4 underlies pathological leakage in hypertensive retina and could be a therapeutic target for treating hypertension-associated retinal edema.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316476DOI Listing
March 2020

Genetic modification increases the survival and the neuroregenerative properties of transplanted neural stem cells.

JCI Insight 2020 02 27;5(4). Epub 2020 Feb 27.

Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

Cell therapy raises hopes high for better treatment of brain disorders. However, the majority of transplanted cells often die soon after transplantation, and those that survive initially continue to die in the subacute phase, diminishing the impact of transplantations. In this study, we genetically modified transplanted human neural stem cells (hNSCs), from 2 distant embryonic stem cell lines (H9 and RC17), to express 1 of 4 prosurvival factors - Hif1a, Akt1, Bcl-2, or Bcl-xl - and studied how these modifications improve short- and long-term survival of transplanted hNSCs. All genetic modifications dramatically increased survival of the transplanted hNSCs. Importantly, 3 out of 4 modifications also enhanced the exit of hNSCs from the cell cycle, thus avoiding aberrant growth of the transplants. Bcl-xl expression provided the strongest protection of transplanted cells, reducing both immediate and delayed cell death, and stimulated hNSC differentiation toward neuronal and oligodendroglial lineages. By designing hNSCs with drug-controlled expression of Bcl-xl, we demonstrated that short-term expression of a prosurvival factor can ensure the long-term survival of transplanted cells. Importantly, transplantation of Bcl-xl-expressing hNSCs into mice suffering from stroke improved behavioral outcome and recovery of motor activity in mice.
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http://dx.doi.org/10.1172/jci.insight.126268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101138PMC
February 2020

Novel Chronic Mouse Model of Cerebral Cavernous Malformations.

Stroke 2020 04 29;51(4):1272-1278. Epub 2020 Jan 29.

From the Université de Paris, NeuroDiderot, Inserm, Paris, France (C.C., M.A., C.D.L., A.-L.L., E.T.-L., G.B.).

Background and Purpose- Cerebral cavernous malformations (CCMs) are vascular malformations of the brain that lead to cerebral hemorrhages. A pharmacological treatment is needed especially for patients with nonoperable deep-seated lesions. We and others obtained CCM mouse models that were useful for mechanistic studies and rapid trials testing the preventive effects of candidate drugs. The shortened lifespan of acute mouse models hampered evaluation of compounds that would not only prevent lesion appearance but also cure preexisting lesions. Indirubin-3'-monoxime previously demonstrated its efficacy to reverse the cardiac phenotype of zebrafish mutants and to prevent lesion development in an acute CCM2 mouse model. In the present article, we developed and characterized a novel chronic CCM2 mouse model and evaluated the curative therapeutic effect of indirubin-3'-monoxime after CCM lesion development. Methods- The chronic mouse model was obtained by a postnatal induction of brain-endothelial-cell-specific ablation of the gene using the inducible -CreER mouse line. Results- We obtained a fully penetrant novel CCM chronic mouse model without any obvious off-target phenotypes and compatible with long-term survival. By 3 months of age, CCM lesions ranging in size from small isolated lesions to multiple caverns developed throughout the brain. Lesion burden was quantified in animals from 1 week to 5 months of age. Clear signs of intracerebral hemorrhages were noticed in brain-endothelial-cell-specific ablation of the gene. In contrast with its preventive effect in the acute CCM2 mouse model, a 20 mg/kg indirubin-3'-monoxime treatment for 3 weeks in 3-month old animals neither had any beneficial effect on the lesion burden nor alleviated cerebral hemorrhages. Conclusions- The brain-endothelial-cell-specific ablation of the gene chronic model is a strongly improved disease model for the CCM community whose challenge today is to decipher which candidate drugs might have a curative effect on patients' preexisting lesions. Visual Overview- An online visual overview is available for this article.
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http://dx.doi.org/10.1161/STROKEAHA.119.027207DOI Listing
April 2020

Impaired endothelium-mediated cerebrovascular reactivity promotes anxiety and respiration disorders in mice.

Proc Natl Acad Sci U S A 2020 01 2;117(3):1753-1761. Epub 2020 Jan 2.

Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, 23562 Lübeck, Germany;

Carbon dioxide (CO), the major product of metabolism, has a strong impact on cerebral blood vessels, a phenomenon known as cerebrovascular reactivity. Several vascular risk factors such as hypertension or diabetes dampen this response, making cerebrovascular reactivity a useful diagnostic marker for incipient vascular pathology, but its functional relevance, if any, is still unclear. Here, we found that GPR4, an endothelial H receptor, and endothelial Gα proteins mediate the CO/H effect on cerebrovascular reactivity in mice. CO/H leads to constriction of vessels in the brainstem area that controls respiration. The consequential washout of CO, if cerebrovascular reactivity is impaired, reduces respiration. In contrast, CO dilates vessels in other brain areas such as the amygdala. Hence, an impaired cerebrovascular reactivity amplifies the CO effect on anxiety. Even at atmospheric CO concentrations, impaired cerebrovascular reactivity caused longer apneic episodes and more anxiety, indicating that cerebrovascular reactivity is essential for normal brain function. The site-specific reactivity of vessels to CO is reflected by regional differences in their gene expression and the release of vasoactive factors from endothelial cells. Our data suggest the central nervous system (CNS) endothelium as a target to treat respiratory and affective disorders associated with vascular diseases.
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http://dx.doi.org/10.1073/pnas.1907467117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983400PMC
January 2020

The Role of Tanycytes in the Hypothalamus-Pituitary-Thyroid Axis and the Possibilities for Their Genetic Manipulation.

Exp Clin Endocrinol Diabetes 2020 Jun 11;128(6-07):388-394. Epub 2019 Dec 11.

Institute for Experimental and Clinical Pharmacology and Toxicology, Lübeck, University of Lübeck, Germany.

Thyroid hormone (TH) regulation is important for development, energy homeostasis, heart function, and bone formation. To control the effects of TH in target organs, the hypothalamus-pituitary-thyroid (HPT) axis and the tissue-specific availability of TH are highly regulated by negative feedback. To exert a central feedback, TH must enter the brain via specific transport mechanisms and cross the blood-brain barrier. Here, tanycytes, which are located in the ventral walls of the 3 ventricle in the mediobasal hypothalamus (MBH), function as gatekeepers. Tanycytes are able to transport, sense, and modify the release of hormones of the HPT axis and are involved in feedback regulation. In this review, we focus on the relevance of tanycytes in thyrotropin-releasing hormone (TRH) release and review available genetic tools to investigate the physiological functions of these cells.
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http://dx.doi.org/10.1055/a-1065-1855DOI Listing
June 2020

CD8 T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome.

Nat Commun 2019 12 18;10(1):5779. Epub 2019 Dec 18.

Centre de Physiopathologie Toulouse-Purpan (CPTP), Université de Toulouse, CNRS, Inserm, UPS, CHU Purpan - BP 3028 - 31024, Toulouse Cedex 3, Toulouse, France.

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8 T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8 T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.
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http://dx.doi.org/10.1038/s41467-019-13593-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920411PMC
December 2019

Metamizole and the risk of drug-induced agranulocytosis and neutropenia in statutory health insurance data.

Naunyn Schmiedebergs Arch Pharmacol 2020 04 7;393(4):681-690. Epub 2019 Dec 7.

Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 236562, Lubeck, Germany.

The non-opioid analgesic metamizole (dipyrone) is used for the treatment of acute and chronic pain and fever. Agranulocytosis is known as a serious adverse drug reaction of metamizole with potentially fatal outcome. However, its frequency is controversially discussed. The aim of our study was to determine the risk of metamizole-associated agranulocytosis and neutropenia using statutory health insurance data. We analyzed data from a large German health insurance fund in the period from 2010 to 2013. Metamizole-exposed subjects were identified and compared to a propensity score-matched control cohort. A total of 630,285 metamizole-treated subjects and 390,830 matched control subjects were included. In the metamizole cohort, ICD codes for agranulocytosis and neutropenia appeared more often than in non-users. The relative risk for drug-induced agranulocytosis and neutropenia (D70.1) was 3.03 (95% confidence interval, 2.49 to 3.69). The risk for developing drug-induced agranulocytosis and neutropenia after metamizole prescription was 1: 1602 (CI 95%, 1:1926 to 1:1371). Our results confirm the risk estimation of previous studies. However, the outcome of our study may be confounded by an association of metamizole treatment and chemotherapy. Therefore, consequences for treatment have to be drawn with care.
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http://dx.doi.org/10.1007/s00210-019-01774-4DOI Listing
April 2020

The impact of endothelial cell death in the brain and its role after stroke: A systematic review.

Cell Stress 2019 Sep 25;3(11):330-347. Epub 2019 Sep 25.

Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.

The supply of oxygen and nutrients to the brain is vital for its function and requires a complex vascular network that, when disturbed, results in profound neurological dysfunction. As part of the pathology in stroke, endothelial cells die. As endothelial cell death affects the surrounding cellular environment and is a potential target for the treatment and prevention of neurological disorders, we have systematically reviewed important aspects of endothelial cell death with a particular focus on stroke. After screening 2876 publications published between January 1, 2010 and August 7, 2019, we identified 154 records to be included. We found that endothelial cell death occurs rapidly as well as later after the onset of stroke conditions. Among the different cell death mechanisms, apoptosis was the most widely investigated (92 records), followed by autophagy (20 records), while other, more recently defined mechanisms received less attention, such as lysosome-dependent cell death (2 records) and necroptosis (2 records). We also discuss the differential vulnerability of brain cells to injury after stroke and the role of endothelial cell death in the no-reflow phenomenon with a special focus on the microvasculature. Further investigation of the different cell death mechanisms using novel tools and biomarkers will greatly enhance our understanding of endothelial cell death. For this task, at least two markers/criteria are desirable to determine cell death subroutines according to the recommendations of the Nomenclature Committee on Cell Death.
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http://dx.doi.org/10.15698/cst2019.11.203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859425PMC
September 2019

Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation.

Sci Transl Med 2019 11;11(520)

Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA.

Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in , , or Disease onset is earlier and more severe in individuals with mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kinase kinase 3 (MEKK3) signaling downstream of Toll-like receptor 4 (TLR4) stimulation by lipopolysaccharide derived from the gut microbiome. These findings suggest a gut-brain CCM disease axis but fail to define it or explain the poor prognosis of patients with mutations. Here, we demonstrate that the gut barrier is a primary determinant of CCM disease course, independent of microbiome configuration, that explains the increased severity of CCM disease associated with PDCD10 deficiency. Chemical disruption of the gut barrier with dextran sulfate sodium augments CCM formation in a mouse model, as does genetic loss of , but not , in gut epithelial cells. Loss of gut epithelial results in disruption of the colonic mucosal barrier. Accordingly, loss of Mucin-2 or exposure to dietary emulsifiers that reduce the mucus barrier increases CCM burden analogous to loss of in the gut epithelium. Last, we show that treatment with dexamethasone potently inhibits CCM formation in mice because of the combined effect of action at both brain endothelial cells and gut epithelial cells. These studies define a gut-brain disease axis in an experimental model of CCM in which a single gene is required for two critical components: gut epithelial function and brain endothelial signaling.
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http://dx.doi.org/10.1126/scitranslmed.aaw3521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937779PMC
November 2019

Nesfatin-1 Acts Centrally to Induce Sympathetic Activation of Brown Adipose Tissue and Non-Shivering Thermogenesis.

Horm Metab Res 2019 Oct 5;51(10):678-685. Epub 2019 Sep 5.

Department of Internal Medicine I, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.

Nesfatin-1 has originally been established as a bioactive peptide interacting with key hypothalamic nuclei and neural circuitries in control of feeding behavior, while its effect on energy expenditure has only recently been investigated. Hence, the aim of this study was to examine whether centrally acting nesfatin-1 can induce β-adrenergic stimulation, which is a prerequisite for the activation of thermogenic genes and heat release from interscapular brown adipose tissue, key physiological features that underlie increased energy expenditure. This question was addressed in non-fasted mice stereotactically cannulated to receive nesfatin-1 intracerebroventricularly together with peripheral injection of the β-adrenoceptor antagonist SR 59230 A, to assess whole-body energy metabolism. Using a minimally invasive thermography technique, we now demonstrate that the thermogenic effect of an anorectic nesfatin-1 dose critically depends on β adrenergic stimulation, as the co-administration with SR 59230 A completely abolished heat production from interscapular brown adipose tissue and rise in ocular surface temperature, thus preventing body weight loss. Moreover, through indirect calorimetry it could be shown that the anorectic concentration of nesfatin-1 augments overall caloric expenditure. Plausibly, central administration of nesfatin-1 also enhanced the expression of DIO2 and CIDEA mRNA in brown adipose tissue critically involved in the regulation of thermogenesis.
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http://dx.doi.org/10.1055/a-0985-4272DOI Listing
October 2019

Antibodies against neural antigens in patients with acute stroke: joint results of three independent cohort studies.

J Neurol 2019 Nov 29;266(11):2772-2779. Epub 2019 Jul 29.

Department of Neuroscience, Comprehensive Stroke Center, Hospital Clinic, Barcelona, Spain.

Background And Purpose: Ischemic stroke (IS) and hemorrhagic stroke (HemS) typically lead to a breakdown of the blood-brain barrier with neural antigen presentation. This presentation could potentially generate destructive auto-immune responses. Pre-existing antineuronal and antiglial antibodies (AA), predominantly NMDA receptor antibodies, have been reported in patients with stroke. This article summarizes three independent prospective studies, the Lübeck cohort (LC), Barcelona cohort (BC), and Heidelberg cohort (HC), exploring the frequency and clinical relevance of AA in patients with acute stroke (AS).

Methods: In all cohorts together, 344 consecutive patients admitted with AS (322 × IS, 22 × HemS) were screened for AA in serum at admission. Clinical outcome parameters as well as a second AA screening were available at 30 days in the LC or at 90 days in the BC. A control group was included in the BC (20 subjects free from neurological disease) and the HC (78 neurological and ophthalmological patients without evidence for stroke).

Results: The rate of positivity for AA was similar in control subjects and AS patients (13%, 95% CI [7%, 22%] vs. 13%, 95% CI [10%, 17%]; p = 0.46) with no significant difference between cohorts (LC 25/171, BC 12/75, HC 9/98). No patient had developed new AA after 30 days, whereas 2 out of 60 patients had developed new AA after 90 days. AA positive patients did not exhibit significant differences to AA negative patients in stroke subtype (LC, BC), initial stroke severity (BC, LC, HC), infarct volume (BC), and functional status at admission (BC, LC, HC) and follow-up (BC, LC).

Conclusions: AS does not induce AA to a relevant degree. Pre-existing AA can be found in the serum of stroke patients, but they do not have a significant association with clinical features and outcomes.
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http://dx.doi.org/10.1007/s00415-019-09470-2DOI Listing
November 2019

Brain endothelial specific gene therapy improves experimental Sandhoff disease.

J Cereb Blood Flow Metab 2020 06 29;40(6):1338-1350. Epub 2019 Jul 29.

Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.

In Tay-Sachs and Sandhoff disease, a deficiency of the lysosomal enzyme β-hexosaminidase causes GM2 and other gangliosides to accumulate in neurons and triggers neurodegeneration. Although the pathology centers on neurons, β-hexosaminidase is mainly expressed outside of neurons, suggesting that gene therapy of these diseases should target non-neuronal cells to reconstitute physiological conditions. Here, we tested in mice, a model of Sandhoff disease, to determine whether endothelial expression of the genes for human β-hexosaminidase subunit A and B (, ) is able to reduce disease symptoms and prolong survival of the affected mice. The brain endothelial selective vectors AAV-BR1-CAG- and AAV-BR1-CAG- transduced brain endothelial cells, which subsequently released β-hexosaminidase enzyme. intravenous administration of the gene vectors to adult and neonatal mice prolonged survival. They improved neurological function and reduced accumulation of the ganglioside GM2 and the glycolipid GA2 as well as astrocytic activation. Overall, the data demonstrate that endothelial cells are a suitable target for intravenous gene therapy of GM2 gangliosidoses and possibly other lysosomal storage disorders.
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http://dx.doi.org/10.1177/0271678X19865917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238384PMC
June 2020

Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan.

Genes (Basel) 2019 07 13;10(7). Epub 2019 Jul 13.

Luebeck Institute of Experimental Dermatology, University of Luebeck, 23562 Luebeck, Germany.

Mitochondrial complex I-the largest enzyme complex of the mitochondrial oxidative phosphorylation machinery-has been proposed to contribute to a variety of age-related pathological alterations as well as longevity. The enzyme complex-consisting proteins are encoded by both nuclear (nDNA) and mitochondrial DNA (mtDNA). While some association studies of mtDNA encoded complex I genes and lifespan in humans have been reported, experimental evidence and the functional consequence of such variants is limited to studies using invertebrate models. Here, we present experimental evidence that a homoplasmic mutation in the mitochondrially encoded complex I gene modulates lifespan by altering cellular tryptophan levels and, consequently, ageing-related pathways in mice. A conplastic mouse strain carrying a mutation at m.4738C > A in lived slightly, but significantly, shorter than the controls did. The same mutation led to a higher susceptibility to glucose intolerance induced by high-fat diet feeding. These phenotypes were not observed in mice carrying a mutation in another mtDNA encoded complex I gene, , suggesting the functional relevance of particular mutations in complex I to ageing and age-related diseases.
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http://dx.doi.org/10.3390/genes10070532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678443PMC
July 2019

Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1.

Nat Med 2019 06 13;25(6):988-1000. Epub 2019 May 13.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier as a possible target to treat age-related neurodegeneration.
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http://dx.doi.org/10.1038/s41591-019-0440-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642642PMC
June 2019