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Nuclear Receptor Activation and Alzheimer's Disease Pathogenesis

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Nuclear Receptor Activation and Alzheimer's Disease Pathogenesis NUCLEAR RECEPTOR ACTIVATION AND ALZHEIMER’S DISEASE PATHOGENESIS By PAIGE ELIZABETH CRAMER Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Dr. Gary Landreth Department of Neurosciences CASE WESTERN RESERVE UNIVERSITY May 2012 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Paige Elizabeth Cramer Doctor of Philosophy Candidate for the ________________________________ degree*. Evan Deneris (Signed )________________________________________________________________ (Chair of the committee) Gary Landreth (signed)_________________________________________________________________ Stephen Maricich _________________________________________________________________ Jerry Silver __________________________________________________________________ Bruce Lamb __________________________________________________________________ March 19,2012 (date) __________________________ *We also certify that written approval has been obtained for any proprietary material contained therein. Dedication Page To Samantha Rodwicz, for forcing me to believe in scientific advancement and to hope for a cure for spinal cord injury. i Table of Contents Dedication Page ............................................................................................................................ i Table of Contents ......................................................................................................................... ii Table of Figures ........................................................................................................................... v Acknowledgements .................................................................................................................... vii Abstract................................................................................................................................1 Chapter 1:Introduction.........................................................................................................3 Introduction .............................................................................................................................. 4 History of Alzheimer’s disease ................................................................................................ 4 Amyloid Precursor Protein and Aβ processing ........................................................................ 6 Genetics of AD and Late onset Alzheimer’s disease ............................................................... 7 Amyloid hypothesis and Aβ homeostasis ................................................................................ 9 Clearance................................................................................................................................ 11 Soluble versus Insoluble Aβ and Cognition ........................................................................... 14 Microglia and the undiseased brain ....................................................................................... 16 Microglia in the AD brain ...................................................................................................... 18 Inflammation: ......................................................................................................................... 22 Microglia and Aβ binding: ..................................................................................................... 23 NSAIDs .................................................................................................................................. 24 Activation Status of Microglia ............................................................................................... 26 Nuclear Receptors .................................................................................................................. 30 ii Retionid X Receptors (RXRs)............................................................................................ 33 Peroxisome Proliferator Activated Receptors (PPARs) ..................................................... 34 Liver X Receptors (LXRs) ................................................................................................. 35 ApolipoproteinE (ApoE) and Alzheimer’s Disease ............................................................... 36 Nuclear Receptors and Alzheimer’s Disease mouse models ................................................. 38 Liver X Receptors .............................................................................................................. 39 Peroxisome Proliferator Activated Receptor ..................................................................... 40 Retinoid X Receptor .......................................................................................................... 42 Retinoic Acid Receptor ...................................................................................................... 44 Current Treatments for AD: ................................................................................................... 45 Focus of the Thesis ................................................................................................................ 46 Chapter 2 :Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer’s Disease..........................................................................................................58 Abstract .................................................................................................................................. 59 Introduction ............................................................................................................................ 60 Materials and Methods ........................................................................................................... 62 Results .................................................................................................................................... 66 Discussion .............................................................................................................................. 73 Chapter 3 : ApoE-directed Therapeutics Rapidly Clear β-amyloid and Reverse Deficits in AD Mouse Models...........................................................................................................93 Abstract: ................................................................................................................................. 95 iii Introduction: ........................................................................................................................... 96 Materials and Methods: .......................................................................................................... 99 Results .................................................................................................................................. 106 Discussion ............................................................................................................................ 113 Chapter 4 : Discussion.....................................................................................................138 NSAIDs as PPARγ agonists: ............................................................................................... 141 Polarization of microglia through PPARγ response elements and other pathways: ............ 143 Infiltration of monocytes and macrophages ......................................................................... 150 Long term bexarotene treatment .......................................................................................... 152 RXR and cytochrome P450 ................................................................................................. 153 Aβ load and Cognitive Impairment Reversal ....................................................................... 156 SUMO .................................................................................................................................. 157 RXR and ApoE isoforms ..................................................................................................... 159 RXR activation in astrocytes ............................................................................................... 160 Nuclear Receptor activation and other diseases ................................................................... 161 Clinical Trials for AD .......................................................................................................... 163 Conclusions .......................................................................................................................... 164 Chapter 5: Works Cited...................................................................................................172 iv Table of Figures Figure 1-1: APP Processing .............................................................................................. 48 Figure 1-2: Aβ aggregation and deposition ...................................................................... 50 Figure 1-3: Intracellular and Extracellular Clearance of sAβ ........................................... 52 Figure 1-4: Nuclear Receptor Activation and Repression ................................................ 54 Figure 1-5:LXR and PPAR are permissive binding partners with RXR .......................... 56 Figure 2-1: Chronic ibuprofen treatment reduces AD-related plaque pathology in B6- R1.40 mice .......................................................................................................................
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