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Download Thesis This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Investigating Nutrient-Sensing Pathways in Ageing Human Neural Stem Cells and Age- Related Cognitive Decline De Lucia, Chiara Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 07. Oct. 2021 Investigating Nutrient-Sensing Pathways in Ageing Human Neural Stem Cells and Age-Related Cognitive Decline Thesis submitted for the degree of Doctor of Philosophy in Neuroscience at King’s College London De Lucia, Chiara 2018 Department of Basic and Clinical Neuroscience Institute of Psychiatry, Psychology and Neuroscience King’s College London Abstract Ageing is associated with changes in cellular and molecular processes including the alteration of stem cell pools. In particular, biological and functional changes observed in ageing neural stem cells (NSCs), are linked to age-related cognitive decline. Recently, the systemic environment has been shown to alter both NSC regulation and age-related cognitive decline. Interestingly, a well-documented and naturally occurring way of altering the composition of the systemic environment is through diet and nutrition. Studies have found an overabundance of nutrients to be detrimental for human and animal health; the presence of specific nutrients as well as the overall increase in calorie or protein intake was shown to overstimulate conserved molecular pathways and to reduce lifespan. Conversely, dietary restriction was found to be the most efficient way of extending an organism’s lifespan. In this study, we examined nutrient sensing pathways in relation to their function in NSCs, ageing and cognition. We focus on the Sirtuin, mTOR and Insulin / Insulin like growth factor- 1 pathways and employ both in vitro and epidemiological methods to assess their contribution to age-related phenotypes. Using a human hippocampal progenitor cell line (HPC) we modelled ageing through treatment with ageing human serum and via pharmacological interventions combined with increased passage number. A semi- automated imaging platform was used for the immunocytochemical quantification of NSC proliferation, differentiation, damage and apoptosis. Further to this, candidate gene selection was preformed through literature search and validated by qPCR to measure gene expression alterations within our ageing models. Results from the in vitro experiments, were used to inform the selection of 9 genes belonging to nutrient-sensing pathways as candidate genes for a role in NSC regulation. Next, we investigated the effects of lifestyle and candidate-gene genotype on cognition using 1633 participants from the adult longitudinal population-based TwinsUK cohort. We report that treatment with human serum is able to induce changes in the HPC model that relate to both the serum-donor’s hippocampal volumes and their cognitive performance. In addition, we report interesting associations between candidate-gene 1 expression and NSC regulation. Our data also revealed increasing passage number causes significant alterations in nutrient-sensing genes and emphasised FOXO3A, NAMPT, PTEN, GRB10 and mTOR as interesting candidates for further ageing research. Finally, epidemiological analysis showed a significant effect of lifestyle on cognition and highlighted associations between SNPs in SIRT1 and ABTB1 and cognitive performance. The results outlined in this thesis support an important role for nutrient-sensing pathways in human NSCs ageing. In addition, we provide support for the use and further development of novel in vitro models to investigate NSCs ageing and to validate existing pathways, uncover new targets and test novel therapies. 2 Acknowledgements I would like to begin by thanking all the incredible people who have supported me throughout my PhD. Firstly, I would like to express my gratitude to Sandrine Thuret for her unwavering support and guidance throughout this project, for encouraging me to pursue my own ideas and for being an excellent role model as a scientist, a supervisor and as a mentor. I am particularly grateful to Petroula Proitsi for guiding me through the previously unknown territory of epidemiological research. Her enthusiasm, availability and expertise were instrumental for the completion of this project. I also thank Richard Dobson for his expertise and help in designing the epidemiological study and Claire Steves and the entire TwinksUK team for providing the cohort data. I would also like to offer a special thanks to Tytus Murphy and to Aleksandra Maruszak for their mentorship in all things cell culture and beyond. Their expertise and patience have been invaluable for my scientific development; I feel extremely lucky to have been taught by two scientists who emphasised technical precision and critical thinking so greatly. I am grateful to everyone at the Wohl institute for their support and willingness to help and for making these years an enjoyable experience. In particular, I would like to thank Demelza Smeeth, Andrea du Preez, Curie Kim and Lucia Dutan Polit for their friendship, advice and assistance during all the ups and downs of a PhD. Edina Silajdzic and Ricky Patel also deserve special mentions for providing writing-up encouragement in the form of limitless snacks and perfectly-foamed lattes. I am also extremely grateful to my parents for supporting through every academic decision and for always encouraging me to pursue my goals. Finally, I would like thank Daisy O’Loughlin for her help in overcoming every hurdle, for her understanding during the countless times plans had to be rearranged to accommodate cell culture and for her constant support and encouragement throughout this project. 3 Table of Contents Abstract ........................................................................................................................ 1 Acknowledgements ....................................................................................................... 3 Table of Contents .......................................................................................................... 4 Table of Figures ............................................................................................................. 9 Table of Tables ............................................................................................................ 14 List of Abbreviations ................................................................................................... 17 1 General Introduction ............................................................................................ 18 1.1 Biogerontology ....................................................................................................... 18 1.2 The ageing brain: focus on the hippocampus ............................................................ 20 Adult neurogenesis .................................................................................................. 22 Effects of ageing on neural stem cell function and neurogenesis ........................... 26 1.3 Impact of diet on neural stem cells .......................................................................... 30 1.4 The role of nutrient-sensing pathways in neural stem cell regulation and ageing ...... 32 mTOR ........................................................................................................................ 34 Insulin ....................................................................................................................... 36 Sirtuins...................................................................................................................... 39 1.5 Epigenetics.............................................................................................................. 43 Epigenetics and nutrition ......................................................................................... 44 Epigenetics, ageing and neural stem cells................................................................ 45 1.6 Conclusions ............................................................................................................. 46 1.7 Summary of introduction ........................................................................................ 47 1.8 Thesis aims and hypotheses .................................................................................... 48 2
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