The Cells of the Oligodendrocyte Lineage Are Differentially Altered by Tau Accumulation and Amyloidosis
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The cells of the oligodendrocyte lineage are differentially altered by tau accumulation and amyloidosis Solène Clémence Aurélie Ferreira Master of Sciences Menzies Institute for Medical Research Submitted in fulfilment of the requirements for the Degree of Doctor of Philosophy University of Tasmania, November 2019 Declaration of Originality This thesis contains no material which has been accepted for a degree or diploma by the Institute or any other University or institution, except by way of background information duly acknowledged in the thesis, and to the best of my knowledge and belief no material previously published or written by another person except where due acknowledgement is made in the text of the thesis, nor does the thesis contain any material that infringes copyright. Solène Ferreira Authority of Access This thesis may be made available for loan and limited copying and communication in accordance with the Copyright Act 1968. Solène Ferreira ii Statement of Co-Authorship All of the work included in this thesis was carried out by Solène Ferreira, with the exception of the electrophysiological data presented in Figure 4.3 and Figure 4.4, which was provided by Dr Kimberley Pitman and Associate Professor Kaylene Young. The following people and institutions contributed to the publication of work undertaken as part of this thesis: Candidate – Solène Ferreira, Menzies Institute for Medical Research, University of Tasmania Author 1 – Kimberley A Pitman, Menzies Institute for Medical Research, University of Tasmania Author 2 – Carlie L Cullen, Menzies Institute for Medical Research, University of Tasmania Author 3 – Kaylene M Young, Menzies Institute for Medical Research, University of Tasmania Author 4 – Shiwei Wang, Menzies Institute for Medical Research, University of Tasmania Author 5 – Nicole Bye, School of Medicine, University of Tasmania Author 6 – Benjamin S Summers, Menzies Institute for Medical Research, University of Tasmania Contribution of work by co-authors for each paper: Paper 1: Located in chapter 3 Solène Ferreira, Kimberley A Pitman, Benjamin S Summers, Shiwei Wang, Kaylene M Young and Carlie L Cullen. Oligodendrogenesis increases in hippocampal grey and white matter prior to locomotor or memory impairment in an adult mouse model of tauopathy. Article published in the European Journal of Neuroscience, 17th March 2020. iii Author contributions: Developed the project: Author 2, Author 3. Carried out the experiments: Candidate, Author 2, Author 3, Author 4, Author 6. Performed statistical analysis and generated the figures: Candidate, Author 1, Author 2, Author 3. Wrote the paper: Candidate, Author 1, Author 2, Author 3. Provided supervision: Author 1, Author 2, Author 3. Obtained the funding: Author 1, Author 2, Author 3. Paper 2: Located in chapter 4 Solène Ferreira, Kimberley A Pitman, Shiwei Wang, Nicole Bye, Benjamin S Summers, Kaylene M Young and Carlie L Cullen. Amyloidosis is associated with the formation of thicker myelin in development and increased adult oligodendrogenesis. Submitted to the Journal of Neuroscience Research, 23rd January 2020. Author contributions: Developed the project: Author 2, Author 3. Carried out the experiments: Candidate, Author 1, Author 3, Author 4, Author 5, Author 6. Performed statistical analysis and generated the figures: Candidate, Author 1, Author 2, Author 3. Wrote the paper: Candidate, Author 1, Author 2, Author 3. Provided supervision: Author 1, Author 2, Author 3. Obtained the funding: Author 1, Author 2, Author 3. iv We, the undersigned, endorse the above stated contribution of work undertaken for each of the published (or submitted) peer‐reviewed manuscripts contributing to this thesis: Signed: ______________________ ______________________ Solène Ferreira Associate Professor Kaylene Young Candidate Primary Supervisor Menzies Institute for Medical Research Menzies Institute for Medical Research University of Tasmania University of Tasmania Date: 28.11.2019 Date: 02.12.2019 ______________________ Professor Alison Venn Head of School Menzies Institute for Medical Research University of Tasmania Date: 02.12.2019 Statement regarding Published Work contained in Thesis The publishers of the papers comprising Chapters 3 and 4 hold the copyright for that content and access to the material should be sought from the respective journals. The remaining non v published content of the thesis may be made available for loan and limited copying and communication in accordance with the Copyright Act 1968. Solène Ferreira Statement of Ethical Conduct The research associated with this thesis abides by the international and Australian codes on human and animal experimentation, the guidelines by the Australian Government's Office of the Gene Technology Regulator and the rulings of the Safety, Ethics and Institutional Biosafety Committees of the University. Ethics Approval No/s 13741 and 16151. Solène Ferreira vi Acknowledgements First, I would like to express my appreciation to the funding bodies that provided my scholarship and allowed this project to happen. I would like to express my immense gratitude to my supervisors, Associate Professor Kaylene Young, Dr Kimberley Pitman and Dr Carlie Cullen for their support during the past four years. I cannot thank you enough for your guidance and assistance. I would like to thank Associate Professor Kaylene Young for giving me the opportunity to be a PhD student in the “glial mutant ninja turtles” lab. I would like to thank Dr Kimberley Pitman for her support during the first year of my PhD. Finally, I would like to particularly thank Dr Carlie Cullen for sharing her expertise, wisdom and great taste in music. You are an amazing mentor, thank you! I must acknowledge all the members of the Young, Foa, Lin and Small labs for their support and feedback during my PhD. I would also like to express my gratitude for their technical help to Dr Olivier Bibari, Dr Nicole Bye and the staff of the animal facility at the Menzies Institute for Medical Research and the Cambridge facility – especially Peta Lawrie, Lynda Mahoney, Lisa Harding and Keri Smith. I would like to thank my fellow PhD students and friends. Sarah, Emma, Cassie, Isabel, Kirianne, Raphael, Andy and the rest of the ‘Vanilla team’ – it was great to share this adventure with you. I would also like to thank my friends and family back home and in Australia for their fantastic support. Camille, Stefan and Lilie – thank you for your visits while I was far away from vii everyone else. To my housemates – thank you for your tremendous encouragement throughout my PhD. Louise – thank you for your support during the first year of my PhD. Jordie – thank you for keeping me sane with your occasional ‘Are you okay?’, being a great housemate and a fantastic friend! Last but not least, I would like to thank the original lab gang – Macarena and Yilan - without you girls, this journey would have been completely different. I am happy we pulled through this experience together as out of this I gained two fabulous friends. From New- Zealand to China, stopping by Chile and France; this is only the beginning! viii Table of Contents Declaration of Originality ...................................................................................................... ii Authority of Access ................................................................................................................. ii Statement of Co-Authorship ................................................................................................. iii Statement regarding Published Work contained in Thesis ................................................. v Statement of Ethical Conduct ................................................................................................ vi Acknowledgements ............................................................................................................... vii Table of Contents .................................................................................................................... ix List of Figures and Tables ..................................................................................................... xv List of Abbreviations .......................................................................................................... xvii Abstract ................................................................................................................................... xx Chapter 1: Introduction .......................................................................................................... 1 1.1. Developmental oligodendrogenesis .............................................................................. 2 1.2. Myelination .................................................................................................................... 6 1.3. Oligodendrogenesis occurs in the healthy adult brain .............................................. 9 1.4. Oligodendrocyte loss with aging and injury ............................................................. 10 1.5. Remyelination is mediated by oligodendrocyte addition to the brain ................... 11 1.6. Alzheimer’s disease ..................................................................................................... 14 1.6.1. Amyloid pathology ............................................................................................... 16 1.6.2. Tau pathology ....................................................................................................... 19 ix 1.7. Progressive