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Proteolysis of the Receptor for Advanced Glycation End Products by Matrix Metalloproteinases

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Proteolysis of the Receptor for Advanced Glycation End Products by Matrix Metalloproteinases Proteolysis of the Receptor for Advanced Glycation End Products by Matrix Metalloproteinases Dissertation Zur Erlangung des Grades Doktor der Naturwissenschaften Am Fachbereich Biologie Der Johannes Gutenberg-Universität Mainz Ling Zhang geb. am 22-10-1972 in Wuhan, China Mainz 2006 i Table of Content Table of Contents Table of Contents ...................................................................................................................................ii 1. Introduction ....................................................................................................................................... 1 1.1 The A β peptide ................................................................................................................................. 1 1.1.1 A β peptide production and its pathologic role in Alzheimer’s disease (AD) ........................... 1 1.1.2 A β peptide clearance from the brain .......................................................................................... 2 1.2 RAGE (receptor for advanced glycation end products) .............................................................. 4 1.2.1 Structure ....................................................................................................................................... 4 1.2.2 Expression patterns ...................................................................................................................... 5 1.2.3 Extracellular ligands and their pathophysiolologic functions .................................................. 5 1.2.4 Intracellular signaling .................................................................................................................. 7 1.2.5 RAGE-Aβ interaction .................................................................................................................. 8 1.2.6 Isoforms of RAGE ........................................................................................................................ 9 1.2.6.1 Full-length RAGE ...................................................................................................................... 9 1.2.6.2 C-terminal truncated RAGE .................................................................................................... 10 1.2.6.3 Soluble RAGE (sRAGE) .......................................................................................................... 10 1.2.6.4 N-truncated RAGE ................................................................................................................... 12 1.3 Protein Ectodomain Shedding ..................................................................................................... 12 1.3.1 Ectodomain shedding ................................................................................................................. 12 1.3.2.1 A disintegrin and metalloproteinases (ADAMs) ...................................................................... 14 1.3.2.2. Matrix metalloproteinases (MMPs) ........................................................................................ 14 2. Aim of the study .............................................................................................................................. 19 3. Materials and Methods ................................................................................................................... 21 3.1 Materials ........................................................................................................................................ 21 3.1.1 Chemicals and Media ................................................................................................................. 21 3.1.2 Enzyme and Kit systems ............................................................................................................ 22 3.1.3 Laboratory instruments and accessories .................................................................................. 23 3.1.4 Solutions, buffers and media ..................................................................................................... 24 3.1.5 Antibodies ................................................................................................................................... 26 3.1.6 Bacterial strains and cell lines ................................................................................................... 28 3.1.7 Plasmids ...................................................................................................................................... 29 3.1.8 Oligonucleotides ......................................................................................................................... 32 3.1.9 Inhibitors and Activators .......................................................................................................... 33 3.2 Methods .......................................................................................................................................... 34 3.2.1 Molecular biology ....................................................................................................................... 34 3.2.1.1 Maintenance of bacterial strains ............................................................................................. 34 3.2.1.2 Preparation of competent bacteria ........................................................................................... 34 3.2.1.3 Transformation of E. coli ......................................................................................................... 34 3.2.1.4 Plasmid Minipreparation ......................................................................................................... 34 3.2.1.5 Plasmid Maxipreparation ........................................................................................................ 35 3.2.1.6 Enzymatic modification of DNA .............................................................................................. 36 3.2.1.7 DNA electrophoresis ................................................................................................................ 37 3.2.1.8 DNA purification ...................................................................................................................... 38 3.2.1.9 DNA Sequencing ...................................................................................................................... 38 3.2.1.10 Polymerase Chain Reaction (PCR) ....................................................................................... 38 3.2.2 Protein biochemical methods .................................................................................................... 40 3.2.2.1 Determination of protein concentration (Bradford assay) ..................................................... 40 3.2.2.2 TCA precipitation of proteins .................................................................................................. 40 3.2.2.3 Chloroform-Methanol precipitation of proteins ..................................................................... 41 3.2.2.4 SDS-polyacrylamide gel electrophoresis ................................................................................. 41 ii Table of Content 3.2.2.5 Western Blot ............................................................................................................................. 42 3.2.2.6 Coomassie staining of polyacrylamide gels ............................................................................. 43 3.2.2.7 Biotinylation of cell surface proteins ....................................................................................... 43 3.2.2.8 Gelatin zymography assay ........................................................................................................ 44 3.2.3 Cell biology methods .................................................................................................................. 44 3.2.3.1 Cell culture ............................................................................................................................... 44 3.2.3.2 Trypsinizing adhesive cells ....................................................................................................... 44 3.2.3.3 Subculture adhesive cells ......................................................................................................... 45 3.2.3.4 Freezing cells ............................................................................................................................ 45 3.2.3.5 Thawing cells ............................................................................................................................ 45 3.2.3.6 Transfect cells with lipofectamine 2000 .................................................................................. 45 3.2.3.7 Transfect cell with DEAE-Dextran reagent ............................................................................ 46 3.2.3.8 Selection of stable transfectants .............................................................................................. 46 3.2.4 Methods for analysis of ectodomain shedding ......................................................................... 46 3.2.4.1 General procedures .................................................................................................................. 46 3.2.4.2 Handling of secretion medium ................................................................................................ 48 3.2.4.3 Handling of cells .....................................................................................................................
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