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The Role of Apoe and Liver X Receptors in Alzheimer's

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The Role of Apoe and Liver X Receptors in Alzheimer's THE ROLE OF APOE AND LIVER X RECEPTORS IN ALZHEIMER’S DISEASE by QINGGUANG JIANG Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Thesis Adviser: Dr. GARY E. LANDRETH Department of Neurosciences CASE WESTERN RESERVE UNIVERSITY AUGUST, 2008 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of _____Qingguang Jiang_____________ _____________________ candidate for the ___________Ph.D._________________degree *. (signed)_________Evan Deneris___________________________ (chair of the committee) ________Bruce Lamb_____________________________ ________Hung-ying Kao___________________________ ________Gary E. Landreth_________________________ _______________________________________________ _______________________________________________ (date) ____5/9/08___________________ *We also certify that written approval has been obtained for any proprietary material contained therein. TABLE OF CONTENTS LIST OF FIGURES ........................................................................................................................... 4 ACKNOWLEDGEMENTS ................................................................................................................ 6 LIST OF ABBREVIATIONS .............................................................................................................. 8 ABSTRACT ................................................................................................................................... 12 Chapter 1 Introduction ..................................................................................... 14 Alzheimer’s Disease ................................................................................................................... 16 Pathology and pathophysiology ............................................................................................ 17 Genetics of AD ....................................................................................................................... 20 Apolipoprotein E .................................................................................................................... 22 Amyloid hypothesis ................................................................................................................ 23 Amyloid homeostasis ................................................................................................................. 25 Aβ generation ........................................................................................................................ 25 Aβ aggregation and deposition .............................................................................................. 26 Aβ clearance from the brain .................................................................................................. 30 Cholesterol homeostasis ............................................................................................................ 42 Cholesterol and AD ................................................................................................................ 42 Cholesterol synthesis ............................................................................................................. 45 Cholesterol uptake and intracellular trafficking .................................................................... 46 Systemic cholesterol transport from the CNS to the periphery ............................................ 51 Inflammation and AD ................................................................................................................. 55 Therapeutic implication in AD ............................................................................................... 56 Nuclear Receptors ...................................................................................................................... 60 Liver X recepters .................................................................................................................... 60 Proxisome proliferation‐activating receptor γ ....................................................................... 63 Anti‐inflammatory transrepression mechanisms of nuclear receptors ................................. 66 The focus of the thesis ............................................................................................................... 74 Chapter 2 ApoE promotes the proteolytic degradation of Aβ ...................... 90 Abstract ...................................................................................................................................... 90 Introduction ............................................................................................................................... 91 1 Methods ..................................................................................................................................... 95 Results ...................................................................................................................................... 103 Microglia efficiently take up and degrade soluble Aβ ......................................................... 103 HDL apolipoproteins enhance the cellular degradation of soluble Aβ by microglia ........... 104 ApoE is essential for efficient intracellular degradation of soluble Aβ by microglia ........... 106 The lipidation status of ApoE influences its ability to promote the intracellular degradation of soluble Aβ. ....................................................................................................................... 107 ApoE lipidation status influences the extracellular degradation of Aβ by IDE .................... 108 The LXR agonist GW3965 reduces plaque pathology and improves memory in Tg2576 mice ............................................................................................................................................. 110 Discussion ................................................................................................................................ 112 Chapter 3 LXR activation does not affect APP processing ........................ 143 Abstract .................................................................................................................................... 143 Introduction ............................................................................................................................. 144 Methods ................................................................................................................................... 148 Results ...................................................................................................................................... 150 LXR activation does not affect synthesis of full‐length APP or active PS1 ........................... 150 LXR activation does not alter the distribution of full‐length APP or active PS1 .................. 151 LXR reduced Aβ levels independently of its anti‐inflammatory activity .............................. 152 Discussion ................................................................................................................................ 153 Chapter 4 LXR activation suppresses microglial inflammatory response and regulates fAβ-stimulated phagocytosis ................................................ 162 Abstract .................................................................................................................................... 162 Introduction ............................................................................................................................. 163 Methods ................................................................................................................................... 165 Results ...................................................................................................................................... 172 LXR agonists inhibit microglial inflammatory response in vitro ........................................... 172 LXR activation accelerates NFκB p65 nuclear export after LPS stimulation ........................ 172 Enhanced p65 nuclear export by LXR activation is due to decreased acetylation of p65 ... 175 LXR agonists relieve the inhibition of microglial phagocytic response to fibrillar Aβ by pro‐ inflammatory cytokines ....................................................................................................... 176 An LXR agonist GW3965 inhibits chronic inflammation in Tg2576 mice ............................. 177 2 Discussion ................................................................................................................................ 178 Chapter 5 Discussion ..................................................................................... 199 Chapter 6 Literature Cited.............................................................................. 212 3 LIST OF FIGURES Figure 1-1 ........................................................................................................... 76 Figure 1-2 ........................................................................................................... 78 Figure 1-3 ........................................................................................................... 80 Figure 1-4 ........................................................................................................... 82 Figure 1-5 ........................................................................................................... 84 Figure 1-6 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