Fluids and Barriers of the CNS | 2019
Abstracts from the 22nd International Symposium on Signal Transduction at the Blood–Brain Barriers
Abstract
s from the 22nd International Symposium on Signal Transduction at the Blood–Brain Barriers Würzburg, Germany. 11–13 September 2019 Published: 11 September 2019 © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. A1 The brain barriers: gatekeepers of CNS immune privilege Britta Engelhardt University of Bern, Theodor Kocher Institute, Bern, Switzerland Correspondence: Britta Engelhardt ‐ [email protected] Fluids Barriers CNS 2019, 16(2): A1 Discoveries leading to an improved understanding of immune surveillance of the central nervous system (CNS) have repeatedly provoked dismissal of the existence of immune privilege of the CNS. Recent rediscoveries of lymphatic vessels within the dura mater surrounding the brain by modern live cell imaging technologies have revived this discussion. Understanding immune privilege of the CNS requires intimate knowledge of its unique anatomy. Employing in vivo and in vitro studies on immune cell migration into the CNS during immune surveillance and neuroinflammation using live cell imaging we have explored the anatomical routes and cellular and molecular mechanisms involved in immune cell trafficking to the CNS. Our findings underscore that endothelial, epithelial and glial brain barriers establish compartments within the CNS that differ strikingly with regard to their accessibility to immune cell subsets. Grant support: This work was supported by the Swiss National Science Foundation, Fidelity International Foundation. A2 Contribution of the blood–brain barrier in Alzheimer’s disease, mouse modelling Amaia Dominguez‐Belloso, Ricardo Figueiredo, Sylvaine Guérit, Sonja Thom, Kavi Devraj, Peter Winter, Stefan Liebner Institute of Neurology (Edinger‐Institute), Johann Wolfgang Goethe‐University Frankfurt, Medical School, Heinrich‐Hoffmann‐Straße 7, 60528, Frankfurt, Germany; GenXPro GmbH, Altenhöferallee 3, 60438, Frankfurt, Germany Correspondence: Amaia.dominguez‐[email protected] Fluids Barriers CNS 2019, 16(2): A2 The blood–brain barrier (BBB) protects the brain from the detrimental influence of various blood-born, endogenous and exogenous substances, and is known to be directly or indirectly involved in the progression of brain pathologies. Although growing evidence points to a major role of the brain vasculature and the BBB in disease progression, little is known about the specific processes taking place at the neurovascular unit (NVU). In order to shed light on the events taking place at the NVU in brain diseases, we performed next generation sequencing, employing the MACE technology, of mouse brain microvessels (MBMVs) from an Alzheimer’s disease (AD) mouse model, harbouring the Thy1-SwDI triple mutation of amyloid precursor protein (APP), and compared it to aged-matched WT mice at 6 and 18 month-of-age. We show that particularly at 6 month-of-age significant regulation of genes involved in cellular junctions, transporters and angiogenic processes takes place in AD mice. Along with these changes in the expression profile we observed that AD mice have memory and BBB deficits at 6 month-of-age by behavioural and tracer experiments with 3-4KD dextrans, respectively, which became aggravated with age. Interestingly, differences in gene expression between AD and WT mice were less pronounced at 18 month-of-age, possibly suggesting that ageing per se leads to pronounced changes at the NVU, and that the AD condition might only push the system to become pathologic. Together, our results point into a major contribution of a hampered BBB in AD but also in ageing, reemphasizing the vascular aspect of AD and highlighting the BBB as a possible therapeutic target. A3 3Rs in blood–brain barrier research: The power of in vitro models Winfried Neuhaus AIT Austrian Institute of Technology GmbH, Vienna, Austria Correspondence: Winfried Neuhaus ‐ [email protected] Fluids Barriers CNS 2019, 16(2): A3 The principles of the 3Rs concept to alternatives to animal testing were first introduced in 1959 by Bill Russel and Rex Burch in their groundbreaking book “The Principles of Humane Experimental Technique”. Basically, it deals with measures to refine, reduce or replace animal experiments with completely animal-free methods. Although the 3Rs are often stated in research proposals as a goal for method development, success in the sense of the 3Rs is very limited. Hardly any method is developed so far that it can really replace an animal experiment specified by the regulations. In the cosmetics industry, animal experiments have been banned in the EU, in toxicology there is a clear trend towards alternative methods, and in the pharmaceutical industry a rethinking of the sensible use of animal experiments is slowly beginning. Nevertheless, the number of animal experiments is increasing, mainly due to the increased use in basic science. It is important to point out that the 3Rs do not serve a purely ethical purpose. With the help of advanced methods, one can pragmatically obtain much better scientific data, especially if one thinks of species differences and considers the translation of data from animal models to humans. In addition, new non-animal methods are cheaper than animal models and can therefore contribute to saving money. In this lecture, an overview of data and new in vitro models in the blood–brain barrier area will be given, which can contribute to the 3Rs, but also their applicability and limitations will be critically examined. In summary, these non-animal models can be used as great, innovative methods to supplement limitations of animal testing and should not be seen as merely replacing Open Access Fluids and Barriers of the CNS Page 2 of 12 Fluids Barriers CNS 2019, 16(Suppl 2):29 and alternatives to animal experiments. In the future, the common, meaningful use of non-animal models with animal experiments could lead to a significant, scientifically meaningful reduction of animal experiments in order to generate even more relevant data for humans. A4 Epigenetic regulation of BBB integrity in stroke Anuska V. Andjelkovic, Svetlana M. Stamatovic, Chelsea M. Phillips, Gabriela Martinez‐Revollar, Richard F. Keep Department of Pathology and Neurosurgery, University of Michigan, Medical School, Ann Arbor, USA Correspondence: [email protected] Fluids Barriers CNS 2019, 16(2): A4 Acute cerebral ischemic injury evokes complex cascade of pathophysiological events at the blood–vascular–parenchymal interface, which evolve over time and space, and result in damage to neuronal cells and edema formation. Stroke survivors usually recover at least some functionality within 3 months, although only 25% return to pre-stroke levels. One problem regarding recovery after stroke is that there are ongoing processes during the chronic phase that increase the risk of recurrent stroke and could also be a solid basis for developing poststroke cognitive impairment (vascular dementia). The new emerging evidence suggest that Blood brain barrier (BBB) recovery is incomplete process which could influent the stroke injury recover, increase risk for the new stroke occurrence and be solid substrata for developing the vascular dementia. Although that several processes are indicated to guide the BBB partial recovery, there are still lack of knowledge whether and how these processes limited the BBB recovery. In the present study we have focused on elucidate the involvement and role of epigenetic mechanism in regulation of post-stroke BBB recovery. The young (3 months) and old mice (18 months) were subject to thromboembolic (TE) stroke based on injection of suspension of platelet-reach microemboli. TE stroke was confirmed and its resolution was followed for 10 days by MRI T2 imaging while BBB permeability was observed and analyzed 1–10 days after stroke using GD-DTPA tracer by MRI T1 imaging. The brain microvessels were collected at day 1 and 10 after TE stroke from area of stroke injury and GD-DTPA hyperpermeability. The isolated brain microvessels from young and old mice were subject of DNA methylation analysis (global DNA methylation assay and Reduced Representation Bisulfite Sequencing (RRBS)) as well histone modification analysis (MODfied Histone peptide Area and ChIP-Seq). Our results indicated profound alteration in DNA methylation and histone monomethylation particularly H3K9, H3K27 and trimethylation (H3K9, H3K79, H3K27) in old mice 10 days after TE stroke. The most affected are proinflammatory and junctional regulator genes. This study provides new information related to the epigenetic regulation of post-stroke BBB and revealed the potential novel therapeutic targets to treat BBB hyperpermeability. A5 Restoring Blood–Brain Barrier Function to Improve Cognition in Alzheimer’s Disease Anika M.S. Hartz, Atcharaporn Ontawong, Yujie Ding, Chutima Srimaroeng, Bjoern Bauer Sanders‐Brown Center on Aging, University of Kentucky, Lexington, USA; Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, USA; Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Division of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, USA Correspondence: Anika MS Hartz ‐ [email protected] Fluids Barriers CNS 2019, 16(2): A5 Introduction: Increasing evidence indicates that blood–brain bar