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The Role of Tau in Amyloid Β Plaque Growth and Formation

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The Role of Tau in Amyloid Β Plaque Growth and Formation THE ROLE OF TAU IN AMYLOID β PLAQUE GROWTH AND FORMATION Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades an der Fakultät für Biologie der Ludwig-Maximilians-Universität München vorgelegt von Hazal Salihoglu München, den 07.06.2019 i Neyi arıyorsan O’sun sen. What you seek is seeking you. Was du suchst, sucht dich. Mevlana (1207-1273) i Diese Dissertation wurde unter der Leitung von Prof. Dr. Jochen Herms am Institut für Neuropathologie der Ludwig-Maximilians-Universität angefertigt und von Prof. Dr. Wolfgang Enard an der Fakultät für Biologie vertreten. Eidesstattliche Erklärung Ich versichere hiermit an Eides statt, dass die vorgelegte Dissertation von mir selbständig und ohne unerlaubte Hilfe angefertigt ist. Hiermit erkläre ich, dass die Dissertation nicht ganz oder in wesentlichen Teilen einer anderen Prüfungskommission vorgelegt worden ist und ich mich anderweitig einer Doktorprüfung ohne Erfolg nicht unterzogen habe. München, den 17.10.2018 Hazal Salihoglu Erstgutachter: Prof. Dr. Wolfgang Enard Zweitgutachter: Dr. rer. nat. Anja Horn-Bochtler Tag der Abgabe: 06.11.2018 Tag der mündlichen Prüfung: 27.05.19 ii Table of contents Table of Contents ACKNOWLEDGEMENTS .................................................................................................... 1 DECLARATION ................................................................................................................... 2 LIST OF FIGURES ............................................................................................................... 3 ABBREVIATIONS ............................................................................................................... 4 ABSTRACT ......................................................................................................................... 5 ABSTRAKT ......................................................................................................................... 6 AIM OF THE STUDY ........................................................................................................... 7 INTRODUCTION ................................................................................................................ 8 Alzheimer`s disease ...................................................................................................... 8 Tau protein (MAPT) .................................................................................................... 13 The role of Tau in AD .................................................................................................. 18 Tau and axonal transport ........................................................................................... 21 Tau knockout mice...................................................................................................... 22 AD mice crossed on Tau deficient background .......................................................... 23 Plaque-associated dystrophies ................................................................................... 25 BACE1 (β-site APP cleaving enzyme) protein ............................................................. 29 The role of BACE1 in dystrophies at plaques.............................................................. 30 The Alzheimer mouse model – APPPS1 ...................................................................... 31 The VGLUT1Venus mouse line ....................................................................................... 32 MATERIALS AND METHODS ........................................................................................... 34 RESULTS .......................................................................................................................... 47 Tau expression is important for plaque growth and the formation of new plaques . 47 Plaques are less compact in tau deficient APPPS1 mice ............................................ 49 Tau expression contributes to the formation of new plaques in close proximity of pre- existing plaques .......................................................................................................... 50 Lack of Tau decreases BACE1 volume fraction around plaques ................................ 51 The decrease in BACE1 volume fraction around plaques was observed in Tau-/- x APPPS1 mice ............................................................................................................... 53 Tau expression modulates APP-positive accumulations in peri-plaque dystrophies 54 iii Table of contents Pre-synaptic transportation of VGLUT1 is not affected by absence of Tau ............... 56 Tau deficiency does not affect the expression of APP, BACE and LAMP1 in pre-synaptic terminals ..................................................................................................................... 58 The anterograde transport of VGLUT1 within axonal dystrophies is not altered by lack of tau ........................................................................................................................... 59 Microglia activation at plaques is indenpendent of the presence of tau .................. 61 BACE1 protein levels are significantly reduced in the whole brains of Tau-/- x APPPS1 .................................................................................................................................... 62 DISCUSSION .................................................................................................................... 64 CONCLUSION .................................................................................................................. 75 CONTRIBUTIONS ............................................................................................................. 76 ACCEPTED PAPERS .......................................................................................................... 77 CURRICULUM VITAE ....................................................................................................... 79 REFERENCES ................................................................................................................... 81 iv Acknowledgements ACKNOWLEDGEMENTS For making my PhD experience worthwhile I would like to thank all of the old and new PhD students and lab members and Jochen Herms for providing me the opportunity to pursue a life long awaited scientific career. I specially thank Elena Montagna for being my reliable friend, for being with me inside and outside of the lab and her sincere advice. Many thanks to Eva Rodrigues, Anna Jaworska, Viktoria Korzhova for making lunch- and coffee breaks and activities joyful and not just a necessary uptake of nutrition. I thank Finn Peters for his collaboration and for his fruitful discussions and positive attitude. Also I would like to thank Severin Filser for his useful comments and corrections on my thesis. My very very special thanks go to my parents (Nesrin Salihoglu, Mustafa Salihoglu) for their year’s long effort to raise me as me. I am sincerely grateful to have them not only for their endless support and but also for being the most reliable humans in the universe. I also thank to my sister, Idil Salihoglu, for teaching me how to stay positive in also difficult moments. I thank my grandmother for teaching me how to be an independent woman in this world. I would not be able to finish this challenging PhD journey without Arjan Dijke. Last but not least, I specially thank him for his endless patience for dealing with the cranky, sensitive and lost child who is me and for his smart jokes which I occasionally understand. I am so grateful to have him as being my lifelong best buddy. 1 Declaration DECLARATION All work included in this thesis was performed at the Ludwig-Maximilians-University under the supervision of Prof. Dr. Jochen Herms. For the project, Hazal Salihoglu performed most of the experimental procedures described. Dr. Finn Peters was involved in the analysis of some of the in vivo imaging data. Novartis performed some biochemical measurements (quantification of Abeta) in one mouse cohort. I confirm that these statements about the contribution of Hazal Salihoglu are accurate. Munich, 07. September 2018 Prof. Dr. Jochen Herms 2 List of Figures LIST OF FIGURES Figure 1. ............................................................................................................................. 10 Figure 2: ............................................................................................................................. 12 Figure 3: ............................................................................................................................. 16 Figure 4. ............................................................................................................................. 23 Figure 5. ............................................................................................................................. 32 Figure 6. ............................................................................................................................. 33 Figure 7. ............................................................................................................................. 40 Figure 8. ............................................................................................................................. 41 Figure 9. ............................................................................................................................. 45 Figure 10. ..........................................................................................................................
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