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PAGE 2 Acknowledgments PAGE 3 Table of Contents 1. Title i 2. Acknowledgements ...ii 3. Table of Contents.iii 4. List of Figures and Graphs ............................v 5. Abstract vii 6. Introduction .1 6.1 Introduction to Traumatic Brain Injury..1 6.2 Microglias Function and role in TBI .... 6.3 Astrocytes Function and role in TBI.....7 6.4 ApoE and its relation to TBI.8 7. Methods and Procedures.38 7.1 Introduction .38 7.2 Experiments 7.2a Apo e 133 149 .38 7.2b APP vs. WT 39 7.2c 2 vs. 4 .. 39 7.2d TBI Severity Study.......40 7.3 General Overview .40 PAGE 4 7.3a TBI infliction.. 40 7.3b Fixation, Embedding and Sectioning 7.3c Staining Techniques .41 7.4d Quantification and Statistical Analysis ..43 8. Results...44 8.1 ApoE 133 149 44 8.1a Microglia Analysis ...44 8.1b Astrocyte Analysis ..45 8.2 APP vs. WT 8.2a 4G8 Analysis 8.2b Astrocyte Analysis .....47 8.3 2 vs. 4 ..47 8.3a Microglia Analysis ...48 8.3b Astro cyte Analysis ..49 8.4 TBI Severity Study ..49 8.4a Astrocyte Analysis ..49 9. Conclusion..52 10. Bibliography.. 54 PAGE 5 List of Figures and Graphs Figures Figure 1 .1 Figure 2 .6 Figure 3 ..10 Figure 4 ..12 Figure 5 ..13 Figure 6 ..15 Figure 7 ..16 Figure 8 ..18 Figure 9 ..19 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Fig ure 17 PAGE 6 Figure 18 Figure 19 Figure 20 Figure 21 Graphs Graph 1 ...44 Graph 2 ...45 Graph 3 ...46 Graph 4 ...47 Graph 5 ...48 Graph 6 ...49 Graph 7 ...50 PAGE 8 1. Introduction 1.1 Introduction to Traumatic Brain Injury Figure 1 Figure 1. PAGE 12 Figure 2. PAGE 13 Figure 2. a c d e d e f g f g 1.2 Microglias functions and role in traumatic brain injury PAGE 14 1.3 Astrocytes function and role in traumatic brain injury PAGE 15 1.4 ApoE and its relation to TBI PAGE 17 Figure 3 Figure 3. a) b) c) d) Figure 3d PAGE 18 p p p Figure 4 PAGE 19 Figure 4. Figure 5 PAGE 20 Figure 5. A) B) C) D) PAGE 21 p p PAGE 22 Fig. 6 Figure 7. Figure 6. PAGE 23 Figure 7. A) B) C) p PAGE 24 Figure 8 p < p PAGE 25 Figure 8 p t in vivo Figure 9 PAGE 26 in vitro Figure 9. in vivo Figure 10 in vivo in vitro PAGE 27 F igure 10. In vivo PAGE 28 p Figure 11a Figure 11b PAGE 29 Figure 11. a) b) p< PAGE 32 Figure 12 Figure 12. p PAGE 33 Figure 13a Figure 13b Figure 14 PAGE 35 Figure 13. a) p b) Figure 14 PAGE 36 Figure 15. Figure 15. A) B) p PAGE 37 p p Figure 16 PAGE 38 Figure 16. PAGE 39 Figure 17 Figure 18 NH CH3CH2O-O OH O Figure 17. Figure 18. PAGE 40 p p<. Figure 19 PAGE 41 Figure 19. p Figure 20 PAGE 42 a) b) Figure 20. a) b) PAGE 43 dementia pugilistica Figure 21 PAGE 44 Figure 21. PAGE 45 2. Methods and Procedures2.1 Introduction 2.2 xperiments E2.2a ApoE 133 149 PAGE 46 2.2b APPvs. WT 2.2c. 2 vs. 4 PAGE 47 2.2d Traumatic Brain Injury Severity Study 2.3 General Overview 2.3.a TBIInfliction 2.3b Fixation, Embedding and Sectioning PAGE 48 2.3c Staining Techniques PAGE 50 2.4d Quantification and Statistical Analysis P PAGE 51 3. Results 3.1 ApoE 133 149 3.1a Microglial Analysis Graph 1. Graph1. P p p PAGE 52 3.1b Astrocyteanalysis Graph 2. Graph 2. P ShamVehicle Cortex vs TBI Vehicle Cortex p <0.01 ShamVehicle Cortex vs TBI Vehicle Hippocampus p <0.001 ShamVehicle Thalamus vs TBI Vehicle Cortex p <0.01 ShamVehicle Thalamus vs TBI Vehicle Hippocampus p <0.001 ShamVehicle Hippocampus vs TBI Vehicle Cortex p <0.01 PAGE 53 ShamVehicle Hippocampus vs TBI Vehicle Hip p <0. 001 ShamApoE Cortex vs TBI Vehicle Cortex p <0.01 ShamApoE Cortex vs TBI Vehicle Hippocampus p <0.001 ShamApoE Thalamus vs TBI Vehicle Cortex p <0.01 ShamApoE Thalamus vs TBI Vehicle Hippocampus p <0.001 ShamApoE Hippocampus vs TBI Vehicle Cortex p <0.05 SgamApoE Hippocampus vs TBI Vehicle Hippocampus p <0.001 TBI Vehicle Hippocampus vs TBI ApoE Cortex p <0.05 TBI Vehicle Hippocampus vs TBI ApoE Thalamus p <0.01 TBI Vehicle Hippocampus vs TBI ApoE Hippocampus p <0.01 3.2APP vs. WT 3.2a 4G8 positive plaquecount Graph 3. Graph 3 P PAGE 54 3 .2b Astroc ytelevels b) c) Graph 4. a) b) c) P p 3 3 .3 2 vs. 4.3a Micro glial analysis PAGE 55 a) b)Graph 5. a) b) Graphs 5a 5b P p PAGE 56 3 .3b GFAP anal ysis Graph 6. Graph 6 P p 3.4Traumatic Br ain Injury Severity Study 3.4a Astrocyte 2 weekand 4 weekanalysis PAGE 57 a) b) Graph 7. a) b) Graphs 7 P PAGE 58 2week Sham Cortex vs 4week TBI 1.3mm Cortex P<0.01 2week Sham Cortex vs 4week TBI 2.0mm Cortex P<0.05 2week Sham Hippocampus vs 4week TBI 1.3mm Cortex P<0.05 2week Sham Hippocampus vs 4week TBI 2.0mm Cortex P<0.05 2week TBI 1.3mm Hippocampus vs 4week TBI 1.3mm Cortex P<0.05 4week TBI 1.3mm Cortex vs 4week Sham Hippocampus P<0.01 4week TBI 1.3mm Cortex vs 4week TBI 1.3mm Hippocampus P<0.01 4week TBI 1.3mm Cortex vs 4week TBI 2.0mm Hippocampus P<0.05 4week TBI 2.0 mm Cortex vs 4week Sham Hippocampus P<0.05 4week TBI 2.0mm Cortex vs 4week TBI 1.3mm Hippocampus P<0.05 4week TBI 2.0mm Cortex vs 4week TBI 2.0 mm Hippocampus P<0.05 PAGE 59 4. Conclusion PAGE 60 5. 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