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Investigating Contributions of Trisomy 21 in Down Syndrome to Alzheimer Disease Phenotypes in a Novel Mouse Cross

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Investigating Contributions of Trisomy 21 in Down Syndrome to Alzheimer Disease Phenotypes in a Novel Mouse Cross Investigating contributions of trisomy 21 in Down syndrome to Alzheimer disease phenotypes in a novel mouse cross A thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy from University College London Xun Yu Choong Department of Neurodegenerative Disease Institute of Neurology University College London 2016 1 Declaration I, Xun Yu Choong, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Acknowledgements The work done in this project was only possible with the support of numerous friends and colleagues, with whom I have grown an incredible amount. Foremost thanks go to Prof. Elizabeth Fisher and Dr. Frances Wiseman, who have been inexhaustibly dedicated supervisors and inspirational figures. Special mention also goes to two unofficial mentors who have looked out for me throughout the PhD, Dr. Karen Cleverley and Dr. Sarah Mizielinska. The Fisher and Isaacs groups have been a joy to work with and have always unhesitatingly offered time and help. Thank you to the Down syndrome group: Olivia Sheppard, Dr. Toby Collins, Dr. Suzanna Noy, Amy Nick, Laura Pulford, Justin Tosh, Matthew Rickman; other members of Lizzy’s group: Dr. Anny Devoy, Dr. Rosie Bunton-Stasyshyn, Dr. Rachele Saccon, Julian Pietrzyk, Dr. Beverley Burke, Heesoon Park, Julian Jaeger; the Isaacs group: Dr. Adrian Isaacs, Dr. Emma Clayton, Dr. Roberto Simone, Charlotte Ridler, Frances Norona. The PhD office has also been a second home in more ways than one, thanks to: Angelos Armen, Dr. Chris McKinnon, Dr. Billy West, Jamie “hypocorism Swag Villain” Miller, Lucianne Dobson, Lucy Sheytanova, Ruchi Kumari, and Alexandra Philiastides. Outside the PhD office, much support has come from Davor Ivankovic, Ania Graca, Andrianos Liavas, Stephanie Bowen, Ana Carolina Saraiva, Steven van de Pavert, James Fairney, Ylonna Kurtzke, Michelle Fong, Sherlynn Chan, Sua Ning, Lim Kang Hong, Pak Shu Hwa and Yarn Shih. Credit and commendation also go to The Espresso Room, for flat whites that never fail. The support staff in the MRC Prion Unit have also played crucial roles. In Queen Square House: Kevin Williams, Ryan Peter, Rosie Baverstock-West, Nato Koiava, and others; in Wakefield Street: Emma Trice, Charlotte Bailey, Michael Brown, Craig Fitzhugh, Jayne Holby, Amanda Dickson, and many more; in the ION Education Unit: Daniela Warr Schori, David Blundred and co. Much of this project has involved learning techniques outside those established in the group, and my gratitude goes to the following for allowing me their time: Prof. Victor Tybulewicz, Prof. Anne Stephenson, Dr. Silvia Purro, Dr. Marifé Cano, Dr. Pavlos Alifragis, Dr. Matthew Ellis, Dr. Daniah Trabzuni and Dr. Vincent Plagnol. In addition, I am hugely appreciative of Dr. Rohan de Silva and Dr. Abraham Acevedo Arozena for a memorable PhD viva. Thank you to the Brain Research Trust for allowing me to embark on the 4-year PhD in Clinical Neuroscience, particularly as an Overseas student. Finally, my greatest thanks go to Ba, Ma and Ning, for having given everything they can for me to be here today. 3 “Onwards and upwards!” 4 Abstract Down syndrome (DS) is a common, complex disorder caused by having an extra copy of human chromosome 21 (trisomy 21). While clinical presentation varies extensively, Alzheimer disease (AD) pathology is found in brains of virtually all people with DS by 40 years. This increases their dementia risk such that one third of the DS population develops AD by 60 years. Therefore DS allows the investigation of pathogenetic mechanisms underlying its clear genetic form of early-onset AD. To model DS in mice, a ‘transchromosomic’ model, Tc1, was generated carrying a freely segregating copy of human chromosome 21 (Hsa21), which is trisomic for ~75% of Hsa21 genes. However, Tc1 is not functionally trisomic for APP. By crossing Tc1 with the J20 model, a transgenic mouse overexpressing mutant human APP that models amyloid deposition, it is possible to compare contributions of trisomy 21 and APP/Aβ overexpression to phenotypes in the genotypically different offspring. The work presented in this thesis therefore characterises AD-related phenotypes in progeny of the Tc1xJ20 cross. I first established a primary cortical culture model from early postnatal Tc1xJ20 pups, which would allow the in vitro observation and manipulation of cortical neurons in a more accessible system compared to in vivo study. To assess the validity and utility of these cultures, they were characterized for APP expression, A production, proportion of neuronal cells in culture and levels of mosaicism for the Hsa21 chromosome. These in vitro phenotypes obtained were compared with relevant in vivo observations in Tc1xJ20 mice. Secondly, to study neuroinflammation and glial reactivity, I developed a digital analysis protocol to systematically quantify morphological characteristics of microglia and astrocytes visualized by immunohistochemistry in Tc1xJ20 brain sections. To further identify AD-related phenotypes that may be differentially influenced by genotype, I annotated data obtained from a pilot RNA sequencing study of Tc1xJ20 hippocampal tissues, identified gene candidates of interest, and explored functions that may be altered by genotype by clustering differentially expressed genes by associated functions. These results therefore allow for discussion and evaluation of the novel Tc1xJ20 model for identifying novel genetic contributions of trisomy 21 on AD phenotypes, apart from APP. 5 Table of Contents Declaration ................................................................................................................... 2 Acknowledgements ....................................................................................................... 3 Abstract ........................................................................................................................ 5 Table of Contents ......................................................................................................... 6 List of Figures ............................................................................................................. 11 List of Tables .............................................................................................................. 14 List of Supplementary Tables...................................................................................... 15 Abbreviations .............................................................................................................. 16 Chapter 1. Introduction ............................................................................................... 20 1.1. Down syndrome ............................................................................................ 20 1.2. Alzheimer disease ........................................................................................ 21 1.2.1. Proteolytic processing of amyloid precursor protein (APP) .................... 22 1.2.2. Genetics of AD ...................................................................................... 24 1.2.2.1. Familial AD (FAD) ........................................................................... 24 1.2.2.2. Sporadic AD (SAD) ......................................................................... 24 1.2.3. The amyloid cascade hypothesis ........................................................... 25 1.3. Alzheimer disease in Down syndrome .......................................................... 26 1.3.1. APP and Aβ phenotypes in DS and AD-DS ........................................... 27 1.3.2. Features distinguishing AD-DS from other forms of AD ......................... 28 1.4. Mouse models of Down syndrome and Alzheimer disease ........................... 30 1.4.1. Mouse models of DS ............................................................................. 30 1.4.2. The transchromosomic Tc1 mouse ........................................................ 34 1.4.3. Considerations when studying AD phenotypes in DS mouse models .... 38 1.5. Mouse models of AD .................................................................................... 39 1.5.1. Transgenic models of AD ...................................................................... 39 1.5.2. The J20 mouse model of APP/A overexpression ................................. 40 1.6. The Tc1xJ20 model of trisomy 21 and APP/Aβ overexpression .................... 44 1.6.1. Trisomy 21 exacerbates mortality associated with APP/Aβ overexpression .................................................................................................... 45 1.6.2. Trisomy 21 exacerbates behavioural deficits associated with APP/Aβ overexpression .................................................................................................... 45 1.6.3. Trisomy 21 accelerates Aβ accumulation .............................................. 48 6 1.6.4. Which genes on Hsa21, other than APP, exacerbate APP/Aβ-related phenotypes? ....................................................................................................... 50 1.6.5. What phenotypes may be studied to investigate the effects of trisomy 21 on age-dependent AD pathology? ....................................................................... 50 1.6.6. How does trisomy 21 alter gene expression and what clues may this yield to pathophysiology? ...........................................................................................
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