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Novel Biological Functions of Apolipoprotein-E

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Novel Biological Functions of Apolipoprotein-E Novel biological functions of apolipoprotein-E David Anthony Elliott Submitted in total fulfilment of the requirements of the degree of Doctor of Philosophy Faculty of Medicine, University of New South Wales May, 2009 To my parents Judy & Ray Elliott II ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….............. SUPERVISOR STATEMENT I hereby certify that all co-authors of the published or submitted papers agree to David Elliott submitting those papers as part of his Doctoral Thesis. Signed …………………………………………….............. Dr Brett Garner Date …………………………………………….............. III ACKNOWLEDGEMENTS Firstly, I would like to thank my supervisor Brett Garner for his much appreciated support and encouragement throughout my candidature. I am also very grateful to my co-supervisor Woojin-Scott Kim for all of his support and assistance. I would also like to extend my appreciation to the rest of my colleagues within the Garner Group, the Prince of Wales Medical Research Institute and the Centre for Vascular Research for their technical advice and, more importantly, for being a great bunch of people to work with. Special thanks to Kayan Tsoi and Sandra Holinkova for assistance in running western blots, Glenda Halliday for provision of human tissue samples and David Jans for expert advice. I am deeply grateful to my father, Ray, and girlfriend, Meagan, for the tremendous amount of love, support and encouragement they haven given to me throughout my candidature. IV ABSTRACT ApoE is a polymorphic protein that has been found to play many different roles in biological processes including lipid transport, neurobiology and immunoregulation. ApoE occurs in the human population in three major isoforms; apoE2, apoE3 and apoE4. The apoE4 isoform has been identified as a major risk factor for several diseases including atherosclerosis and Alzheimer’s Disease, therefore a greater understanding of apoE biology is highly sought after. In my thesis, I have investigated several novel aspects of apoE biology. I have identified an association between increased apoE expression and apoptosis in a neuronal cell type and demonstrated that apoE becomes enriched within the neuronal apoptotic debris, consistent with a possible role for apoE in facilitating apoptotic debris clearance. A possible anti-apoptotic role of apoE in macrophages was assessed by reducing or eliminating apoE expression using siRNA and cells isolated from apoE knockout animals, respectively. The removal of apoE did not alter overall sensitivity to apoptosis, however, it did significantly increase staurosporine-induced caspase-3 activation. In other studies, the poorly understood accumulation of apoE within the nucleus was found to be enhanced during serum starvation and to localise in intra-nuclear structures that are distinct from inter- chromatin granule clusters. Analysis of apoE within the human brain revealed a correlation between fragmentation and the apoE3 isoform which was independent from AD status and brain region examined. Additionally, a portion of brain apoE3 was found to be present in the form of disulphide-linked dimers. Collectively, these studies have further expanded the current knowledge of apoE biology in terms of its association with apoptosis, nuclear localization and structural differences between the apoE3 and apoE4 isoforms in the human brain. V TABLE OF CONTENTS Originality statement ...……………………………………………………. III Acknowledgements .………………………………………………………. IV Abstract …………….…………….…………….…………………………... V Publications arising from this thesis ……...………….………………….… IX Journal articles ……….…………………...………….………………….… IX Conference abstracts ……...………………………….………………….… IX Oral presentations ………………...………….………………….… IX Poster presentations ………………..………….………………….… X Abbreviations ……...………….…………………………..…………….… XII 1. INTRODUCTION …………………………………………….…………. 1 1.1 GENERAL INTRODUCTION TO APOLIPOPROTEIN-E ……………. 1 1.1.1 Structure ……………………………………………………………..… 1 1.1.2 Regulation of apoE …………………………………………………..… 5 1.1.2.1 Cellular expression …………………………………………….…..… 5 1.1.2.2 Intracellular transport and processing ………………….…………….. 5 1.1.2.3 Transcriptional regulation …………………………………...……..… 7 1.1.3 ApoE is a multifunctional protein ………………………………..…..… 8 1.1.3.1 Lipid transport ………………………………………….…………..… 8 1.1.3.2 Immunomodulation ………………………………………………..… 11 1.1.3.3 Receptor interactions ………………………………………………… 14 1.2 ApoE AND MACROPHAGE BIOLOGY ……………………………..… 18 1.2.1 The macrophage ……………………………………………………...… 18 VI 1.2.2 Atherosclerosis ………………………………………..……………...… 19 1.3 ASSOCIATION OF apoE WITH APOPTOSIS ………………………..... 20 1.3.1 Introduction to apoptosis …………………………………….………..... 20 1.3.2 A role of apoE in apoptosis? ………………………………………….... 25 1.4 ROLE OF apoE IN NEUROBIOLOGY ………………………................. 26 1.4.1 CNS lipid transport ……………………………………….…................. 26 1.4.2 Cognitive function ………………………............................................... 27 1.4.3 Role in nerve regeneration and repair ………………………................. 28 1.4.4 Neuronal expression of apoE ………………….……………................. 28 1.5 ApoE AND ALZHEIMER’S DISEASE ……...………………................. 30 1.5.1 Alzheimer’s disease background ……………………………................. 30 1.5.2 Generation of amyloid plaques …………………...…………................. 32 1.5.3 Alzheimer’s disease risk factors ……………………….......................... 35 1.5.3.1 Early-Onset Alzheimer’s Disease ………………………..................... 35 1.5.3.2 Late-Onset Alzheimer’s Disease ………………….………................. 35 1.5.4 ApoE in the Alzheimer’s Disease brain ………….…………................. 36 1.5.4.1 ApoE levels in the AD brain ………………………............................ 36 1.5.4.2 Interactions with amyloid beta ……………………………................. 38 1.5.4.3 Role of apoE in Neurofibrillary Tangle formation …………………... 41 1.5.4.4 Proteolysis of apoE ………………………………………………….. 41 VII 2. AIMS OF THIS THESIS ……………………………………………….. 44 3. RESULTS ………………………………….…………………………….. 45 3.1 RESULTS SUMMARY ………………………………………………… 45 3.2 PUBLICATIONS ……………………………………………………..… 48 3.2.1 Publication I …………………………………………………...……… 48 3.2.2 Publication II ………………………………………………………..… 54 3.2.3 Publication III ………………………………………………….……… 64 3.2.4 Publication IV ……………………………………………….………… 74 4. GENERAL DISCUSSION …………………………………………….. 128 4.1 POSSIBLE ROLES OF apoE IN APOPTOSIS ……………………….. 128 4.1.1 Cell survival …………………………………………………………. 128 4.1.2 Clearance of apoptotic debris ……………………………………….. 130 4.2 NUCLEAR TRAFFICKING OF apoE ……………….……………….. 131 4.3 STRUCTURAL DIFFERENCES BETWEEN apoE ISOFORMS IN THE HUMAN BRAIN …………………………………..…..…….. 132 4.3.1 Fragmentation of apoE3 in the human brain ……………….……….. 133 4.3.2 Mechanism of apoE proteolysis in the brain ………………………... 136 4.3.3 Biological function of apoE fragments? …………………………….. 138 4.3.4 ApoE disulfide linked dimers ……………………………………….. 139 5. MAJOR CONCLUSIONS ……………………………………………. 141 6. REFERENCES ………………………………………………..………. 142 VIII PUBLICATIONS ARISING FROM THIS THESIS Journal articles 1. David A. Elliott, Woojin S. Kim, David A. Jans and Brett Garner. (2007) Apoptosis induces neuronal apolipoprotein-E synthesis and localization in apoptotic bodies. Neuroscience Letters 416: 206-210. 2. David A. Elliott, Woojin S. Kim, David A. Jans and Brett Garner. (2008) Macrophage apolipoprotein-E knockdown modulates caspase-3 activation without altering sensitivity to apoptosis. Biochimica et Biophysica acta 1780:145-53. 3. Woojin S. Kim , David A. Elliott , Maaike Kockx, Leonard Kritharides, Kerry-Anne Rye, David A. Jans and Brett Garner. (2008) Analysis of apolipoprotein-E nuclear localization using green fluorescent protein and biotinylation approaches. The Biochemical Journal 409: 701-9. 4. David A. Elliott, Kayan Tsoi, Sandra Holinkova, Sharon L. Chan, Woojin S. Kim, Glenda M. Halliday, Kerry-Anne Rye, David A. Jans and Brett Garner. Isoform- specific processing of apolipoprotein-E in the human brain. Revised manuscript accepted for publication in Neurobiology of Aging, February 2009. Currently in print. Conference abstracts Oral presentations: 1. Elliott, D. A. ‘Isoform-specific processing of apoE in the human brain’ Kioloa Neuroscience Colloquium, April 2008. IX 2. Elliott, D. A., Kim, W. S. and Garner, B. ‘Exploring the potential role of apolipoprotein-E in apoptosis’ Dementia, Ageing and Neurodegeneration DISeases Group (DANDIS) conference held at the Prince of Wales Medical Research Institute, January 2006. Poster presentations: 3. Elliott, D. A., Kim, W. S. and Garner, B. ‘Post-translational modifications of apolipoprotein-E in the human brain’ International Conference on Alzheimer’s Disease, Chicago, USA, July 2008. 4. Elliott, D. A., Kim, W. S. and Garner, B. ‘Post-translational modifications of apolipoprotein-E in the human brain’ Australian Neuroscience Society 28th
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