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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/ Functional Interactions between Peroxisome Proliferator- Activated Receptor-Gamma and polipoprotein E Isoforms in the Regulation of Neural Functions in Models of Insulin Resistance-Relevance to Alzheimer’s Disease To, Alvina 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: 08. Oct. 2021 This electronic theses or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Title: Functional Interactions between Peroxisome Proliferator- Activated Receptor-Gamma and polipoprotein E Isoforms in the Regulation of Neural Functions in Models of Insulin Resistance- Relevance to Alzheimer’s Disease Author: Alvina To 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 LICENSE AGREEMENT This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. http://creativecommons.org/licenses/by-nc-nd/3.0/ You are free to: Share: 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. Functional Interactions between Peroxisome Proliferator- Activated Receptor-Gamma and Apolipoprotein E Isoforms in the Regulation of Neural Functions in Models of Insulin Resistance-Relevance to Alzheimer’s Disease Alvina To A thesis submitted for the degree of Doctor of Philosophy at the Institute of Psychiatry, University of London King’s College London, Institute of Psychiatry, London SE5 8AF ! "! ABSTRACT Insulin resistance, part of the metabolic syndrome, is associated with type 2 diabetes mellitus (T2DM) and increased risk for Alzheimer’s disease (AD). The !4 allele of APOE is the greatest genetic risk factor for sporadic, late onset AD, and is also associated with risk for T2DM. The thiazolidinediones (TZDs), PPAR" agonists, are peripheral insulin sensitisers used to treat T2DM and have been found to slow cognitive decline in mild to moderate AD patients. Since it is not yet clear how PPAR" affect insulin signalling processes in AD, I investigated the effects of the TZD, pioglitazone, on A# metabolism and tau phosphorylation in high fat diet (HFD)-induced insulin resistant mice carrying the human APOE!3 or APOE!4 genes. HFD reduced tau phosphorylation at specific epitopes, independent of APOE genotype. Pioglitazone treatment reduced tau phosphorylation, in an APOE-dependent manner, with the APOE!3 mice being most responsive. Examination of HFD effects on the cortical transcriptome revealed increased expression of the ABCA1 gene in mice lacking APOE and the ADRA2A gene in APOE!4 mice. ABCA1 and apoE are associated with A# clearance in the brain, while ADRA2A suppresses insulin secretion and polymorphisms in this gene is associated with T2DM risk. Erk1/2, p38, JNK, and calcineurin were differentially expressed between APOE!3 and APOE!4 mice on HFD indicating these kinases and phosphatases may contribute to the increased risk for AD imparted by APOE!4. I have identified APOE allele-dependent effects of PPAR" agonists on tau phosphorylation and have identified diet and APOE allele-dependent effects on gene expression that relate to AD. Further work is needed to validate current findings and to further elucidate the mechanism. A better understanding of the relative importance of brain and peripheral insulin resistance will greatly improve our understanding of the disease process and also aide the rational design of therapeutics to halt its progression. ! #! ACKNOWLEDGEMENTS First and foremost, I would like to thank my supervisors Simon Lovestone, Joern Schroeder and Diane Hanger for their invaluable guidance and support throughout my PhD. I have been lucky in receiving help and inspiration from individuals within the department of Old Age Psychiatry, the Institute of Psychiatry in general, as well as collaborations outside the borders of this institute. As such, I would like to begin by expressing my gratitude to Richard Killick, Elena Ribe, Claudie Hooper, Abdul Hye, Mirsada Causevic and Michelle Lupton for generously sharing their expertise and research skills. I would also like to thank Caroline Johnston, Katie Lunnon and Kuang Lin for their help and advice on the transcriptomics work presented in chapter 7. Furthermore, I would like to extend my thanks to Judy Latcham, Michael Fullylove, Jason Smith and Sylvia Fung at GlaxoSmithKline for their excellent animal husbandry, which supported a vital part of the work presented in this thesis. I am also greatful for the generous support of the BBSRC and GlaxoSmithKline in their funding of this studentship. Last but not least, I would like to thank my family and friends for their support and encouragement throughout the four years of my PhD. ! $! TABLE OF CONTENTS ABSTRACT ........................................................................................................ 2 ACKNOWLEDGEMENTS .................................................................................. 3 TABLE OF CONTENTS ..................................................................................... 4 LIST OF FIGURES AND TABLES..................................................................... 8 PUBLICATIONS ARISING FROM THIS WORK.............................................. 12 ABBREVIATIONS ............................................................................................ 13 CHAPTER 1: Introduction .............................................................................. 18 1.1 Alzheimer’s disease ..........................................................................................19 1.1.1 Amyloid beta (A#) pathology and the discovery of amyloid precursor protein (APP).....................................................................................................................20 1.1.1.1 The proteolytic processing of APP and the production of A#.............................21 1.1.1.2 Intracellular A# ...................................................................................................25 1.1.1.3 The amyloid cascade hypothesis .......................................................................28 1.1.2 Tau pathology...............................................................................................31 1.1.2.1 Tau structure, isoforms and function..................................................................32 1.1.2.2 Tau phosphorylation...........................................................................................34 1.1.2.3 Pathological functions of tau ..............................................................................36 1.1.3 Calcium and AD ...........................................................................................39 1.2 Apolipoprotein E (ApoE) and AD .....................................................................42 1.2.1 ApoE structure, isoforms and function .........................................................44 1.2.2 ApoE and A# pathology................................................................................50 1.2.3 ApoE and tau pathology ...............................................................................53 1.3 The metabolic syndrome, type 2 diabetes and AD ........................................55 1.3.1 Type 2 diabetes and AD...............................................................................56 1.3.2 Insulin and memory ......................................................................................58 1.3.3 Insulin signalling and AD pathology .............................................................60 1.3.3.1 The insulin signalling pathway
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