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Multidisciplinary Analysis of Biological Effects of Novel Analogs of The UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE des Sciences de la vie et de la santé (ED 414) INSERM UMR_S U1119 Biopathologies de la Myéline, Neuroprotection et Stratégies Thérapeutiques THÈSE En cotutelle avec l´Albert-Ludwigs-Universität Freiburg, Allemagne présentée par : Mona KAROUT soutenue le : 30 Septembre 2015 pour obtenir le grade de : Docteur de l’université de Strasbourg Discipline / Spécialité : Neurosciences Multidisciplinary analysis of biological effects of novel analogs of the neurosteroid allopregnanolone: evidence for a proliferative, neurogenic and ne uroprote ctive action THÈSE dirigée par : M. MENSAH-NYAGAN Ayikoé, Guy Professeur, Université de Strasbourg, France M. HOFMANN Hans-Dieter Professeur, Albert-Ludwigs-Universität Freiburg, Allemagne RAPPORTEURS : M. FISCHBACH Karl-Friedrich Professeur, Albert-Ludwigs-Universität Freiburg, Allemagne M. SCHWEMMLE Martin Professeur, Albert-Ludwigs-Universität Freiburg, Allemagne AUTRES MEMBRES DU JURY : M. DUFOUR André Professeur, Université de Strasbourg, France Mme. PATTE-MENSAH Christine Docteur, Université de Strasbourg, France !"# $%&'(%# To my parents A mes parents Acknowledgement ACKNOWLEDGEMENT First of all, I would like to express my appreciation and gratitude to all members of my thesis committee, Prof. Karl-Friedrich Fischbach, Prof. Martin Schwemmle, Prof. André Dufour and Dr. Christine Patte-Mensah for taking the time to evaluate my thesis. Furthermore, I would like to express my deepest gratitude to my two PhD supervisors Prof. Ayikoé Guy Mensah-Nyagan and Prof. Hans-Dieter Hofmann. I am very thankful to you Prof. Mensah-Nyagan for giving me a great opportunity for performing this joint French-German PhD. Thank you very much for the continuous support, for your patience, enthusiasm, passion for research and immense knowledge. Thank you for pushing me to give my best. Your guidance helped me a lot during my thesis. Thank you for always caring on academic and personal level; I really appreciate your concern and compassion towards me especially when I was at the hospital. It meant so much to me! I am very thankful to you Prof. Hofmann for welcoming me in your lab and especially for the switch in the language! Thank you a lot for your help with all my administrative papers when I came to Freiburg, for finding me a place to live and even going with me to open a bank account. I will never forget your kindness and your unlimited help. Thank you for your patience, understanding, discussions and encouragement. I am very grateful for all the effort, time, support and help during my thesis writing. And once again I am very sorry for all the stress! Dear Matthias, I am deeply thankful for all the help, knowledge and guidance during these three years. Thank you for being available and willing to listen and help every day. Thank you for teaching me all the methods. This work would never be done without you. I guess we will never forget all the animals we had to perfuse! Thank you a lot for your time and all the trips to Strasbourg. This PhD work is a part of an international research program, INTERREG IV Upper Rhine, within the framework of the Offensive Sciences on neuroprotection and neurogenesis led by the consortium Neuro-Rhine which includes laboratories from the three neighboring countries (France, Germany and Switzerland) of the Upper Rhine Valley. I gratefully acknowledge the funding sources for my scholarship and the grant of our collaborative project: INTERREG, European Regional Development Fund (ERDF), Offensive Sciences, Région Alsace and Baden Württemberg region. I would like to thank all the members of the consortium Neuro-Rhine for the scientific exchange. It was a great pleasure to meet and to work with all of you. A special thanks to Dr. Michel Miesch and Dr. Philippe Geoffroy, our drug dealers! Thanks to Dr. Chantal Mathis and Aurélia Ces for all the behavioral studies and for great communication and super planning. A Big thanks to Birgit and Simona for their excellent technical support and help. Acknowledgement I would like to thank Stephanie Kraft for being a great colleague and a nice friend. You are the best German-English translator! Thank you for all the help in everything: scientific experiments and all the German documents. Thanks to you, I learned a lot of new techniques. Good luck in everything and I am sure you will be a very bright scientist in the near future. I would like also to thank Imane Lejri for her friendship, support and the many discussions (scientific or not) that we had during the past three years. In addition, I would like to thank all the members of Prof. Mensah Nyagan´s lab in Strasbourg and Prof. Hofmann´s lab in Freiburg (Sarah, Judith and Gaby). Life would not be the same without great friends which became family to me. I am grateful to Strasbourg that made me meet people like you guys: André, Yara, Ranine and Laurene. I will never forget our funny, crazy and amazing time together. You were there for me in my happy and sad moments. THANK YOU! Andy, thank you for simply being there in the past 8 years. Your support helped me to make it through it all especially when I doubted myself. Last but not the least, I am so lucky to have such a wonderful family: my adorable parents Wajih and Vera and my charming sisters Zeinab, Jeannette and Vika. I cannot find enough words to thank you. I appreciate that you all bore my bad temper and helped me to overcome my stress in the past three years. Despite the distance, you made me feel so close to you! Dear Dad and mum, thank you for everything: your love, kindness, encouragement and especially the unconditional support in all my decisions. And most importantly for the fate and the trust you have in me. I am here today because of an extraordinary family. You were the source of my motivation and a reminder of what is truly important in life. I LOVE YOU! Table of contents Table of contents FIGURES AND TABLES LISTS ................................................................................ 1 1. Figures list ........................................................................................................... 1 2. Tables list ............................................................................................................ 3 ABREVIATIONS ........................................................................................................ 4 INTRODUCTION ........................................................................................................ 9 1. Neurodegenerative diseases ............................................................................... 9 2. Alzheimer´s disease .......................................................................................... 10 2.1. Neurofibrillary tangles ................................................................................ 11 2.2. Amyloid peptide ......................................................................................... 12 2.2.1. The non-amyloidogenic pathway ........................................................ 12 2.2.2. The amyloidogenic pathway ............................................................... 13 2.2.3. Enzymes implicated in proteolytic processing of APP ........................ 14 2.2.4. The amyloid cascade hypothesis and its evolution ............................. 14 2.2.5. Toxicity of amyloid beta oligomers ...................................................... 15 2.2.6. Amyloid beta induced apoptotic pathways .......................................... 17 3. Adult neurogenesis in the rodent brain .............................................................. 20 3.1. Neural stem cells in the adult mammalian brain ......................................... 21 3.2. The Subventricular Zone (SVZ) ................................................................. 22 3.3. The Subgranular Zone (SGZ) .................................................................... 23 3.4. Immunohistological markers for proliferation events, gliogenesis and neurogenesis in the adult hippocampus ............................................................ 26 3.4.1. Markers for neural stem cells .............................................................. 26 3.4.2. Markers for proliferatively active cells ................................................. 26 3.4.3. Markers for the neuronal lineage ........................................................ 27 3.4.4. Markers for the glial lineage ................................................................ 28 3.5. Functional significance of adult neurogenesis ............................................ 28 3.6. Adult neurogenesis during aging and neurodegenerative diseases ........... 29 3.7. Contribution of neural stem/progenitor cells to brain repair ........................ 31 4. Neurosteroids .................................................................................................... 32 4.1. Definition .................................................................................................... 32 4.2. Biosynthesis ............................................................................................... 33 4.3. Mechanisms of action ................................................................................ 34 5. Allopregnanolone (AP) ...................................................................................... 36 5.1. Biosynthesis ............................................................................................... 36 5.2. Mechanisms of action ...............................................................................
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