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Effects of A-Beta Immunotherapy and Omega-3 Fatty Acid Administration in Alzheimer's Transgenic Mice Maren T

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Effects of A-Beta Immunotherapy and Omega-3 Fatty Acid Administration in Alzheimer's Transgenic Mice Maren T University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School 2006 Effects of A-beta immunotherapy and Omega-3 fatty acid administration in Alzheimer's transgenic mice Maren T. Jensen University of South Florida Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the American Studies Commons Scholar Commons Citation Jensen, Maren T., "Effects of A-beta immunotherapy and Omega-3 fatty acid administration in Alzheimer's transgenic mice" (2006). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/2573 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Effects of A-beta Immunotherapy and Omega-3 Fatty Acid Administration in Alzheimer’s Transgenic Mice by Maren T. Jensen A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Biology College of Arts and Sciences University of South Florida Major Professor: Gary Arendash, Ph.D. Huntington Potter, Ph.D. Sidney Pierce, Ph.D. Brian Livingston, Ph.D. Date of Approval: March 6, 2006 Keywords: Active Vaccination, Fish Oil, DHA, Cognitive Performance, Plaque Deposition © Copyright 2006, Maren T. Jensen Acknowledgements I thank Dr. David Morgan for providing the animals utilized in the Aβ immunotherapy study and Dr. Marcia Gordon for her involvement in the animal vaccinations and Aβ immunostaining. I would also like to thank Purina Mills Test Diet for providing the low omega-3, omega-3-deficient, high n-3 and high n-6 fatty acid diets and Barrow-Agee Laboratories for analyzing all four of the fatty acid diets. In addition, I would like to thank Dr. Norman Salem and Dr. Nahed Hussein for their determination of fatty acid levels from the frontal cortex. Table of Contents List of Tables ..................................................................................................................... iii List of Figures..................................................................................................................... v Introduction......................................................................................................................... 1 Alzheimer’s Disease Background................................................................................. 1 AD Behavioral Deficits................................................................................................. 2 AD Pathology................................................................................................................ 5 Cerebral Atrophy, Neuronal Loss........................................................................... 5 Neuritic Plaques...................................................................................................... 7 Neurofibrillary Tangles......................................................................................... 12 Genetics of AD ........................................................................................................... 16 Diagnosis of AD ......................................................................................................... 18 Risk Factors for AD.................................................................................................... 25 Treatment of AD......................................................................................................... 29 Animal Models............................................................................................................ 36 PDAPP Transgenic Mice. ..................................................................................... 38 APPsw Transgenic Mice....................................................................................... 44 APP/PS1 Transgenic Mice.................................................................................... 52 AD Vaccination .......................................................................................................... 55 In Vitro Studies..................................................................................................... 55 Active Aβ Immunotherapy. .................................................................................. 56 Passive Aβ Immunotherapy.................................................................................. 64 Aβ Immunotherapy in Humans. ........................................................................... 69 Omega-3 Fatty Acids ................................................................................................. 70 General Background. ............................................................................................ 70 Dietary Manipulation of n-3 and n-6 Fatty Acids................................................. 75 Human Studies Involving Fatty Acids.................................................................. 83 Neurochemical Effects of n-3 Fatty Acids............................................................ 89 Effects of n-3 Fatty Acids on 2nd Messengers. ..................................................... 97 Behavioral Effects of n-3 Fatty Acids in Animals.............................................. 104 Statement of Purpose ................................................................................................ 115 Materials and Methods.................................................................................................... 117 Life-long Vaccination Study..................................................................................... 117 Omega-3 Fatty Acid Study- Survival Analysis ........................................................ 121 i Omega-3 Fatty Acid Study- Behavioral, Pathologic and Neurochemical Assessments........................................................................ 126 Behavioral Testing Procedures ................................................................................. 136 Statistical Analysis.................................................................................................... 143 Results............................................................................................................................. 146 Life-long Vaccination Study..................................................................................... 146 Sensorimotor- and Anxiety-based Tasks. ........................................................... 147 Cognitive-based Tasks........................................................................................ 151 Aβ Histopathology.............................................................................................. 167 FA and Correlation Analyses.............................................................................. 169 DFA..................................................................................................................... 172 Omega-3 Fatty Acid Study- Survival Analyses........................................................ 176 Omega-3 Fatty Acid Study: Behavioral, Pathologic and Neurochemical Assessments........................................................................ 181 Sensorimotor- and Anxiety-Based Tasks............................................................ 184 Cognitive-based Tasks........................................................................................ 188 Cytokine Levels .................................................................................................. 211 Hippocampal Aβ levels....................................................................................... 211 Fatty Acid Brain Tissue Levels........................................................................... 216 Correlations and Multimetric Analyses .............................................................. 222 Discussion....................................................................................................................... 238 Aβ Vaccination Discussion....................................................................................... 238 Omega-3 Discussion ................................................................................................ 248 Survival Analysis................................................................................................ 249 Behavioral, Pathologic and Neurochemical Assessments. ................................. 251 Overall Conclusions.................................................................................................. 267 References....................................................................................................................... 269 ii List of Tables Table 1. Summary of behavioral studies involving n-3 deficiency or supplementation to rodents………………………………………….……..107 Table 2. Percent fatty acid composition of total fat for standard chow, low omega-3 diet and omega-6 deficient diets……………...………...125 Table 3. Percent fatty acid composition of total fat for standard chow, high omega-3 and high omega-6 diets…………………………....…...130 Table 4. A summary of transgenic and immunotherapy at both 4½-6 and 15-16½ month test points………………………...………………..146 Table 5. Total Aβ and compact Aβ for Tg+/Con and Tg+/Aβ at 17 months of age within frontal cortex and hippocampus……………………168 Table 6. Factor Loadings of behavioral measures, with and Without pathologic measures………………………………...……………….171
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