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Coversheet for Thesis in Sussex Research Online A University of Sussex DPhil thesis Available online via Sussex Research Online: http://sro.sussex.ac.uk/ This thesis is protected by copyright which belongs to the author. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Please visit Sussex Research Online for more information and further details A’s effect on long term memory: A top-down approach in Lymnaea stagnalis LENZIE KATHERINE FORD A thesis submitted for the degree of Doctor of Philosophy University of Sussex July 2015 Declaration The work presented in this thesis is entirely my own, except where acknowledgement and reference was made. This thesis has not been, and will not be, submitted in whole or in part to another University for the award of any other degree. Lenzie Ford (July 2015) Acknowledgements I would like to express my sincere gratitude to my supervisors George Kemenes and Louise C. Serpell for their intellectual support, mentorship, patience, and time. Their positive influence played a very important role in shaping not only my PhD experience, but also my scientific career. For this, I am extremely grateful. I would like to thank Dr. Michael Crossley, Dr. Tom Williams, and Devkee Vadukul for their work referenced in this thesis. I would also like to thank the past and present members of the G. Kemenes, L.C. Serpell, I. Kemenes, K. Staras, P. Benjamin, J.R. Thorpe, and S. Morley labs; whilst there are too many to name here, many colleagues offered both academic and friendly support which has been invaluable to my experience at Sussex. Finally, I would like to thank my wonderful family, friends, and partner for their never- ending love and support; as well as the American Friends of the University of Sussex for their financial support. I Table of contents List of figures and tables V Abbreviations IX Abstract XIIV Publications XVI 1. General Introduction 1 1.1 Learning and memory 1 1.1.1 Synaptic and nonsynaptic plasticity 1 1.1.2 Dendritic alterations and new synaptic growth 5 1.1.3 Invertebrates used in learning and memory studies 6 1.2 Lymnaea stagnalis, a learning and memory model 8 1.2.1 Circuitry involved in feeding and memory 10 1.2.2 Molecular signalling cascades involved in memory 12 1.3 Alzheimer’s Disease 15 1.3.1 Neuropathological characteristics of AD 16 1.4 Amyloid 17 1.4.1 Amyloid precursor protein (APP) 17 1.4.2 Amyloid peptide 20 1.4.3 A’s involvement in AD 22 1.4.4 Oligomeric A 23 1.4.5 A affects nonsynaptic plasticity 26 1.5 Thesis outline 26 2. Materials and methods 28 II 2.1 Experimental animals 28 2.2 Preparation and systemic application of A peptides 28 2.3 Single-trial food-reward classical (CS+US) conditioning 29 2.4 TEM immunolabelling 30 2.5 Cell death and apoptosis measurements 31 2.6 SDS-PAGE and membrane immunolabelling 32 2.7 Measurement of protein concentration 37 2.8 Preparation and imaging of AlexaFluor 488 tagged A 1-42 37 2.9 Formic acid extracted haemolymph preparation 38 2.10 TEM negative stain 39 2.11 Behavioural pharmacology 39 2.12 S35-methionine labelling 40 2.13 Chromatin extraction 40 2.14 Enzyme-linked immunosorbent assay (ELISA) 41 2.15 Statistical analysis 42 3. Lymnaea stagnalis as a novel behavioural model for Amyloid research 43 3.1 A 1-42 and A 25-35 disrupts long term memory after 24 hour in vivo incubation 43 3.2 Animals treated with 1 M A 1-42 or 0.1 mM A 25-35 do not exhibit neuronal death after 24 hours in vivo incubation 47 3.3 Animals treated with 1 M A 1-42 and 0.1 mM A 25-35 have significantly decreased levels of PSD-95 in comparison to trained and vehicle-injected animals after 24 hours in vivo incubation 51 3.4 1 M A 1-42 or 0.1 mM A 25-35 does not affect III memory acquisition or early consolidation 53 3.5 Discussion 57 4. A structure and location can be monitored and quantified in Lymnaea stagnalis 61 4.1 A antibodies label untreated snail brain 62 4.2 A unique combination of peptide-tagging and antibodies distinguishes exogenous from endogenous signal 64 4.3 A can be extracted from animals, imaged, and quantified, indicating structural forms that exist after 24 hours in vivo incubation 69 4.4 A can be measured in snail brain tissue 74 4.5 Behavioural and structural studies of an oligomerically-produced A 25-35 76 4.6 Discussion 81 5. A 1-42 and 25-35 disrupts CREB in trained Lymnaea stagnalis 83 5.1 Training and A treatment does not alter general protein levels at 48 hours post-training 85 5.2 CREB is modified by treatment with A at the 24 hour post-injection/ 48 hour post-training time point 91 5.3 Discussion 101 6. A 1-42 and 25-35 disrupts CREB-signalling cascades in trained Lymnaea 103 stagnalis 6.1 Receptors involved in memory and/or CREB-signalling pathways may be disrupted by treatment with A at the 24 hour post-injection/ 48 hour post-training time point. 108 IV 6.2 Second messengers involved in CREB-signalling pathways are not disrupted by treatment with A at the 24 hour post-injection/ 48 hour post-training time point 120 6.3 Kinases involved in CREB-signalling pathways are disrupted by treatment with A at the 24 hour post-injection/ 48 hour post-training time point. 123 6.4 Discussion 140 7. General Discussion 143 7.1 Future experiments 156 References 160 Appendix 217 V List of Figures and Tables Figure 1.1 Sequence of events in chemical transmission. 3 Figure 1.2 Model of excitatory glutamatergic synapse after learning-related 4 enhancement. Figure 1.3 Photograph of Lymnaea brain. 9 Figure 1.4 Diagram of feeding movements, cellular location, and circuitry. 11 Figure 1.5 CREB-signalling cascades involved in Lymnaea LTM. 14 Figure 1.6 APP processing. 19 Figure 1.7 Examples of cross- structure. 21 Table 2.1 Optimisation for antibodies used in this thesis. 35 Figure 3.1 A 1-42 and A 25-35 disrupt long term memory after 24 hour in vivo incubation. 46 Figure 3.2 A 1-42 and A 25-35 treated animals do not exhibit morphological indicators of cell death after 24 hours in vivo incubation. 48 Figure 3.3 A 25-35 and A1-42 do not cause apoptosis after 24 hour incubation. 50 Figure 3.4 PSD-95 levels significantly decrease in animals treated with 1 M A 1-42 or 0.1 mM A 25-35 for 24 hours in vivo. 52 Figure 3.5 A 1-42 and A 25-35 do not disrupt memory acquisition or early consolidation when measured 24 hours post-training. 54 Figure 3.6 A 1-42 and A 25-35 disrupt memory measured 48 hours post-injection. 56 Figure 4.1 Antibodies which label A oligomers bind to naïve snail brains. 63 VI Figure 4.2 AlexaFluor 488-tagged A 1-42 (1 M and 50 M) reaches the snail brain within 24 hours of in vivo incubation. 66 Figure 4.3 AlexaFluor 488-tagged A 1-42 reaches the snail brain within 24 hours of in vivo incubation. 67 Figure 4.4 AlexaFluor 488-tagged A1-42 enters the snail brain by 24 hour in vivo incubation at 1 M and 25 M concentrations. 68 Figure 4.5 Oligomeric A is found in the haemolymph after 24 hour in vivo incubation. 70 Figure 4.6 Representative silver stained gels of formic acid extraction fractions. 71 Figure 4.7 A 1-42 and A 25-35 aggregates differently when allowed to incubate in normal saline solution for 24 hours, conducted by Dr. Tom Williams. 73 Figure 4.8 Nu4 and Nu1 label A in the snail brain. 75 Figure 4.9 Oligomeric A 25-35 does not cause behavioural deficits when 1 M is allowed to incubate in vivo for 24 hours. 77 Figure 4.10 Oligomerically prepared A 25-35 fibrillises when allowed to incubate in normal saline solution for 24 hours, microscopy conducted by Devkee Vadukul. 78 Figure 4.11 Oligomeric A is not found in the haemolymph of oligomerically prepared A 25-35-treated animals after 24 hour in vivo incubation, microscopy conducted by Devkee Vadukul. 80 Figure 5.1 General protein levels do not change 48 hours after training or 24 hours after A injection. 86 VII Figure 5.2 Anisomycin does not disrupt 48 hour memory recall. 89 Figure 5.3 A and training do not affect protein synthesis between the 24 hour injection and 48 hour testing time point of the behavioural protocol. 90 Figure 5.4 Basic sample preparation and western blotting indicate no change in total CREB levels across groups. 93 Figure 5.5 Lack of H3 labelling in the cytosolic fraction and lack of tubulin labelling in the nuclear fraction show that the chromatin extraction procedure was successful. 95 Figure 5.6 Nuclear protein extraction removes non-specific signal from CREB and pCREB antibodies in Lymnaea brain tissue samples. 97 Figure 5.7 A 25-35 decreases total CREB labelling in nuclear fractions.
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