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Evaluating the Potential Therapeutic Role of Angiotensin Converting Evaluating the Potential Therapeutic Role of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers for Alzheimer’s Disease using a Drosophila Model by Sarah Gomes A thesis submitted in conformity with the requirements for the degree of Master of Science Institute of Medical Science University of Toronto © Copyright by Sarah Gomes 2017 Evaluating the Potential Therapeutic Role of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers for Alzheimer’s Disease using a Drosophila Model Sarah Gomes Master of Science Institute of Medical Science University of Toronto 2017 Abstract Presenilins (PS) play a role in familial Alzheimer’s disease (AD) and Notch signalling. In a genetic screen looking for modifiers of APP but not Notch, we identified Drosophila orthologs of Angiotensin Converting Enzyme (ACE). Interestingly, ACE polymorphisms are associated with AD and Apo-E, the best characterized risk factor for late-onset AD. Moreover, ACE inhibitors (ACE-I) delayed the onset of cognitive impairment and neurodegeneration in mice and humans. However, it remains unclear why ACE-I are beneficial in AD. Here, we explore the link between PS and ACE in a Drosophila model using genetics and pharmacology. We found that ACE disruption does not affect Notch related phenotypes. Moreover, we found that ACE-I and Angiotensin Receptor Blockers are beneficial in an AD Drosophila model. Since inhibition of ACE has no detrimental effects on Notch and modulates AD related phenotypes, it could provide an important therapeutic target for AD. ii Acknowledgments I would like to begin by thanking my supervisor, Gabrielle Boulianne, for her support and guidance. She has not only taught me how to think like a scientist, but also how to create a work- life balance. She has been tremendously proactive and supportive of my professional goals and always instilled confidence in my abilities, especially when graduate school tested me. Without her leadership, this thesis would not have been possible and I am deeply grateful to her. Thank you to my committee members Lucy Osborne, Howard Mount, and Freda Miller, for providing valuable scientific insight to my project and for challenging me, it has made me become a better scientist. I would also like to thank past and present Boulianne lab members, Mike Garroni, Irene Trinh, Dragan Gligorov, Kostas Iliadi, Nataly Iliadi, Oxana Gluscencova, Greg Chernomas, Alex Lee, Dave Knight, Sili Liu, and Attey Rostami for all of their help and friendship. Everyone in the lab has helped me in some way, from intellectual or technical support, to coffee breaks on long days in the lab. I am so grateful to have had the opportunity to work with and learn from all of you. I am forever indebted to my family for their unconditional love and support. My parents, siblings, grandparents, aunts, uncles, and cousins have all brought me so much joy throughout my life and always encouraged me to pursue my dreams. To my mom, thank you for always supporting my love of science from when we would study high school biology together, to your continued encouragement today; you are my unwavering inspiration and I am so grateful to you. To my dad, thank you for always supporting my decisions and for helping me realize my goals by being my loudest cheerer (and for reading this thesis!). Thank you to my siblings, Katelyn and John, and to my friends, for reminding me not to take life too seriously and have some fun. I would also like to give a big thank you to Raed Makhlouf, your endless love and encouragement gave me strength when graduate school pushed my limits. Finally, I would like to dedicate this thesis in loving memory of my Avó, Filomena Gomes (03/05/1931 – 12/24/2016). iii Statement of Contributions The author, Sarah Gomes, completed all work presented in this thesis. iv Table of Contents Acknowledgments .......................................................................................................................... iii Statement of Contributions ............................................................................................................ iv Table of Contents ............................................................................................................................ v List of Tables ................................................................................................................................. ix List of Figures ................................................................................................................................. x List of Abbreviations .................................................................................................................... xii Chapter 1 ......................................................................................................................................... 1 1 Introduction ................................................................................................................................ 1 1.1 Alzheimer’s Disease ........................................................................................................... 1 1.1.1 Incidence and Clinical Presentation ........................................................................ 1 1.1.2 AD genetics ............................................................................................................. 3 1.1.2.1 APP Mutations .......................................................................................... 3 1.1.2.2 PS1 Mutations ........................................................................................... 6 1.1.2.3 PS2 Mutations ........................................................................................... 6 1.1.2.4 Risk Factor Genes ..................................................................................... 6 1.1.3 Cellular & Molecular Mechanisms ......................................................................... 7 1.1.3.1 Amyloid Beta and Tau .............................................................................. 7 1.1.3.1.1 Non-amyloidogenic pathway ........................................................................... 9 1.1.3.1.2 Amyloidogenic pathway ................................................................................ 10 1.1.3.1.3 The γ-Secretase Complex .............................................................................. 12 1.1.4 Current AD Standard of Care ................................................................................ 15 1.2 The Link Between ACE and AD ...................................................................................... 16 1.2.1 The Use of ACE-I and ARB in Humans ............................................................... 20 v 1.2.2 In vitro Analysis of ACE and Aβ .......................................................................... 25 1.2.3 In vivo Analysis of ACE and AD Models ............................................................. 25 1.3 Drosophila as a model organism ...................................................................................... 30 1.3.1 Drosophila Life Cycle .......................................................................................... 30 1.3.2 Drosophila development ....................................................................................... 32 1.3.3 Drosophila genetics and genomics ....................................................................... 35 1.3.3.1 Drosophila ACE like factors .................................................................. 35 1.3.4 Genetic tools ......................................................................................................... 37 1.3.5 Drosophila models of AD ..................................................................................... 40 1.3.6 Drug testing using Drosophila .............................................................................. 41 1.3.6.1 The Genetic Interaction between ACE, PS, and APP ............................ 42 1.4 Rationale ........................................................................................................................... 44 Chapter 2 ....................................................................................................................................... 45 2 Objective and Hypotheses ........................................................................................................ 45 2.1 Main Objective .................................................................................................................. 45 2.2 Specific Hypotheses .......................................................................................................... 45 2.2.1 Test whether ACE and ATR disruption will modify phenotypes associated with the Notch signalling pathway ........................................................................ 45 2.2.2 Test how ACE-I and ARB administration affects AD-related phenotypes .......... 45 Chapter 3 ....................................................................................................................................... 48 3 Materials and Methods ............................................................................................................. 48 3.1 Drosophila Genetics ......................................................................................................... 48 3.1.1 Notch Genetics ...................................................................................................... 48 3.1.2 APP Genetics
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