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Table of Contents The role of the amyloid precursor protein (APP) in protein homeostasis and neuroprotection Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften vorgelegt beim Fachbereich 14 der Johann Wolfgang Goethe -Universität in Frankfurt am Main von ARPITA KUNDU aus Kalkutta, Indien Frankfurt 2017 (D 30) vom Fachbereich 14 der Johann Wolfgang Goethe - Universität als Dissertation angenommen. Dekan: Prof. Dr. Michael Karas Gutachter: Prof. Dr. Donat Kögel Prof. Dr. Jochen Klein` Datum der Disputation: TBD To my parents, husband and daughter Table of Contents Table of Contents Abbreviations .................................................................................................................................... ix Tables ............................................................................................................................................... xi Figures .............................................................................................................................................. xi Overview and Summary ..................................................................................................................... 1 Zusammenfassung ............................................................................................................................ 7 1 Introduction .............................................................................................................................. 13 1.1 Alzheimer’s Disease ........................................................................................................ 13 1.1.1 APP family members ............................................................................................... 16 1.1.2 APP structure ........................................................................................................... 17 1.1.3 Biochemical processing of APP ............................................................................... 18 1.1.4 APP function ............................................................................................................ 20 1.2 Cell death ......................................................................................................................... 22 1.2.1 Apoptosis ................................................................................................................. 22 1.2.2 Necrosis ................................................................................................................... 25 1.2.3 Autophagy ................................................................................................................ 26 1.3 BAG1 and BAG3 .............................................................................................................. 27 1.4 Role of stress signaling pathways in neurodegeneration and apoptosis ......................... 29 1.5 Role of APP in survival cascade and stress signaling ..................................................... 31 1.6 Aim of the Thesis ............................................................................................................. 33 2 Materials ................................................................................................................................... 37 2.1 Cell lines ........................................................................................................................... 37 2.2 Animals ............................................................................................................................ 37 2.3 Cell culture medium ......................................................................................................... 38 2.4 Chemicals ........................................................................................................................ 40 2.5 Buffers and Solutions ....................................................................................................... 40 2.6 Antibody ........................................................................................................................... 44 2.7 Oligoneucleotides for cDNA synthesis and qPCR ........................................................... 45 2.8 Enzymes and recombinant proteins ................................................................................ 46 2.9 Inhibitors and drugs ......................................................................................................... 46 2.10 Kits ................................................................................................................................... 47 2.11 Software ........................................................................................................................... 47 2.12 Equipment and Other Instruments ................................................................................... 48 3 Methods ................................................................................................................................... 53 3.1 Cell biological techniques ................................................................................................ 53 3.1.1 Culture conditions .................................................................................................... 53 Table of Contents 3.1.2 Determination of Cell Number and Seeding of Cells ............................................... 53 3.1.3 Cryopreservation and thawing of cells ..................................................................... 53 3.2 Preparation of Hippocampal Neurons .............................................................................. 54 3.3 Transfection of Plasmid .................................................................................................... 55 3.4 Induction of stress ............................................................................................................ 56 3.5 Analysis of proteins .......................................................................................................... 57 3.5.1 Preparation of cell lysates ........................................................................................ 57 3.5.2 Determination of protein concentration .................................................................... 57 3.5.3 SDS-PAGE ............................................................................................................... 58 3.5.4 Western Blot ............................................................................................................. 58 3.5.5 Coomassie staining of polyacrylamide gels ............................................................. 59 3.5.6 Immunodetection ...................................................................................................... 59 3.6 Immunostaining ................................................................................................................ 59 3.7 Nucleic acid techniques ................................................................................................... 60 3.7.1 Isolation of RNA ....................................................................................................... 60 3.7.2 Determination of RNA concentration........................................................................ 60 3.7.3 cDNA synthesis ........................................................................................................ 60 3.7.4 Quantitative real-time polymerase chain reaction (qPCR) ....................................... 61 3.8 SUC-LLVY-AMC Assay .................................................................................................... 61 3.9 FACS Analysis ................................................................................................................. 62 3.10 Subcellular fractionation and immunodetection of cytochrome c ..................................... 63 3.11 Purification of sAPPα, sAPPβ and E1 from yeast P. pastoris .......................................... 64 4 Results ..................................................................................................................................... 67 4.1 Purification of sAPPα, sAPPβ and E1 from P. pastoris ................................................... 67 4.2 Neuroprotective properties of sAPPα ............................................................................... 69 4.3 Recombinant sAPPα and APP-E1 domain activate the PI3K/Akt survival pathway ........ 73 4.4 sAPPα alters the expression levels of Akt downstream proteins only in the presence of holo-APP ...................................................................................................................................... 74 4.4.1 sAPPα induces the phosphorylation of FoxO3a and inhibits its nuclear translocation. ............................................................................................................................ 74 4.4.2 sAPPα and E1 decreases Bim expression under serum and glucose deprivation .. 77 4.4.3 sAPPα and E1 increases Bcl-xL and Mcl-1 expression under serum and glucose deprivation ................................................................................................................................ 79 4.4.4 Effect of sAPPα treatment on cytochrome c release from mitochondria ................. 81 4.4.5 Effect of sAPPα and E1 on Bax-Bak activation........................................................ 82 4.5 Modulation of protein homeostasis by sAPPα ................................................................. 83 4.5.1 sAPPα prevents
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