Distribution of Secretory Phospholipase Group XIIA in the CNS and its Role in Lipid Metabolism and Cognition EE SZE MIN (B.Sc (Hons), NUS) SUPERVISOR: ASSOCIATE PROFESSOR LO YEW LONG A THESIS SUBMITTED FOR THE DEGREE OF MASTER OF SCIENCE DEPARTMENT OF ANATOMY YONG LOO LIN SCHOOL OF MEDICINE NATIONAL UNIVERSITY OF SINGAPORE 2013 Declaration DECLARATION I hereby declare that the thesis is my original work and it has been written by me in its entirety I have duly acknowledged all the sources of information which have been used in the thesis This thesis has also not been submitted for any degree in any university previously _ Ee Sze Min 14 January 2013 I Acknowledgements ACKNOWLEDGEMENTS I wish to express my deepest appreciation and gratitude to my two supervisors, Associate Professor Lo Yew Long, Department of Anatomy, National University of Singapore, who extended utmost support to my entire project; to my co-supervisor, Associate Professor Ong Wei Yi, Department of Anatomy, National University of Singapore, for suggesting this study, and for his patient guidance and encouragement throughout the course of the study His immense patience, enthusiasm and stimulating discussion have been invaluable in the accomplishment of this thesis I would like to express my appreciation to all staff members and fellow postgraduate students in the Histology Laboratory, Neurobiology Programme, Centre for Life Sciences and Anatomy Department who have help me in one way of another - Miss Chan Yee Gek and Mdm Wu Ya Jun for their assistance in electron microscopy and Mdm Ang Lye Gek Carolyne, Mdm Teo Li Ching Violet and Mdm Dilijit Kour D/O Bachan Singh for their secretarial assistance I would also like to extend my appreciation to my fellow colleagues in the lab, Chew Wee Siong, Chia Wan Jie, Kazuhiro Tanaka, Kim Ji Hyun, Lee Hui Wen Lynette, Loke Sau Yeen, Ma May Thu, Ng Pei Ern Mary, Poh Kay Wee, Tan Yan, Yang Hui and Yap Mei Yi Alicia for their contributions to make this project successful I would also like to thank Associate Professor Markus R Wenk and Dr Shui Guanghou for their support in lipidomic analysis II Table of Contents TABLE OF CONTENTS CONTENTS PAGE Declaration Page I Acknowledgements II Table of Contents III Summary VII List of Tables IX List of Figures X Abbreviations XII SECTION I - INTRODUCTION 1.0 Phospholipase A2 1.1 Cytosolic Phospholipase A2 1.2 Calcium Independent Phospholipase A2 1.3 Secretory Phospholipase A2 1.3.1 sPLA2-IB 1.3.2 sPLA2-IIA 10 1.3.3 sPLA2-IIC 11 1.3.4 sPLA2-IID 11 1.3.5 sPLA2-IIE 12 1.3.6 sPLA2-IIF 12 1.3.7 sPLA2-III 13 1.3.8 sPLA2-V 14 1.3.9 sPLA2-X 15 1.4 1.3.10 sPLA2-XIIA 15 1.3.11 sPLA2-XIIB 17 PLA2 Function in the Brain 18 1.4.1 19 Neurotransmitter Release III Table of Contents 1.4.2 Long-Term Potentiation 20 1.4.3 Membrane Repair 21 1.4.4 Neurite Outgrowth and Regeneration 22 1.4.5 Inflammatory and Anti-Inflammatory Processes 23 1.4.6 Neurodegeneration 23 1.5 Arachidonic Acid in the Brain 24 1.6 PLA2 Receptors 26 1.7 Aims of the present study 27 SECTION II – EXPERIMENTAL STUDY 28 CHAPTER – EXPRESSION PROFILE OF VARIOUS PLA2 ISOFORMS IN THE CNS 2.1.1 Introduction 29 2.1.2 2.1.3 2.1.4 30 Materials and Methods 32 2.1.2.1 Real-Time PCR 32 2.1.2.2 Western Blot Analyses 33 Results 35 2.1.3.1 Differential Expression of sPLA2-XIIA mRNA in the CNS 35 2.1.3.2 Differential Expression of PLA2 Isoforms in the Prefrontal Cortex 36 2.1.3.3 Differential Expression of PLA2 Isoforms in the Hippocampus 37 2.1.3.4 Western Blot Analyses of sPLA2-XIIA Protein Expression in the Brain 38 Discussion CHAPTER – LOCALIZATION OF GROUP XIIA sPLA2 IN VARIOUS REGIONS OF THE BRAIN 41 43 2.2.1 Introduction 44 2.2.2 Materials and Methods 46 2.2.2.1 46 Immunohistochemistry IV Table of Contents 2.2.2.2 Electron Microscopy 2.2.3 Results 46 48 2.2.3.1 sPLA2-XIIA Localization in Forebrain under Light Microscopy 48 2.2.3.2 sPLA2-XIIA Localization in Hindbrain under Light Microscopy sPLA2-XIIA Localization in the Cortex under Electron Microscopy 49 2.2.3.3 2.2.4 Discussion 51 52 CHAPTER – CHANGES IN PREFRONTAL CORTICAL LIPID PROFILE OF GROUP XIIA sPLA2 KNOCKDOWN RATS 2.3.1 Introduction 2.3.2 Materials and Methods 55 56 59 2.3.2.1 Intracortical Injection of Antisense Locked Nucleic Acid 59 2.3.2.2 Western Blot to show Knockdown of sPLA2-XIIA 59 2.3.2.3 Lipid Extraction 60 2.3.2.4 Lipid Analyses using Liquid Chromatography/Mass Spectrometry 60 2.3.3 Results 62 2.3.3.1 Western Blot Analyses of Antisense LNA Injected Rats 62 2.3.3.2 Lipidomic Analyses 64 2.3.3.2.1 Phosphatidic Acid 66 2.3.3.2.2 Phosphatidylcholine and Lysophosphatidylcholine 67 2.3.3.2.3 Phosphatidylethanolamine and Lysophosphatidylethanolamine 69 2.3.3.2.4 Phosphatidylinositol and Lysophosphatidylinositol 71 2.3.3.2.5 Phosphatidylserine and Lysophosphatidylserine 72 2.3.3.2.6 Sphingolipid and Sphingomyelin 73 V Table of Contents 2.3.3.2.7 Ceramide and Glucosyl-Ceramide 74 2.3.3.2.8 Gangliosides 75 2.3.4 Discussion CHAPTER – FUNCTIONAL STUDIES OF GROUP XIIA sPLA2 IN KNOCKDOWN RATS 76 78 2.4.1 Introduction 79 2.4.2 Materials and Methods 82 2.4.2.1 Attentional Set-Shifting Task 82 2.4.2.2 Passive Avoidance 85 2.4.3 Results 86 2.4.3.1 Attentional Set-Shifting Task 86 2.4.3.2 Passive Avoidance 88 2.4.4 Discussion 90 SECTION III - CONCLUSION 93 SECTION IV – FUTURE STUDIES 97 SECTION V - REFERENCES 99 VI Summary SUMMARY Phospholipases A2 (PLA2) catalyze the hydrolysis of membrane phospholipids to produce free fatty acids and lysophospholipids, which have important functions in cell signaling To date, however, little is known about differential expression and physiological functions of PLA2 isoforms in specific brain regions The present study was carried out to determine differential expression of PLA2 isoforms in the prefrontal cortex (PFC) of the rat brain Real time RT-PCR results indicated that sPLA2-XIIA had greater mRNA expression than iPLA2-VI or cPLA2-IVA in all brain regions, or compared to other sPLA2 isoforms, in the PFC and hippocampus Western blots showed a 24kDa band in different regions of the adult brain, and high levels of sPLA2-XIIA protein expression were detected in the PFC, striatum and thalamus The enzyme was immunolocalized to neurons, and electron microscopy showed that sPLA2-XIIA is present in axon pre-terminals or growth cones that did not form synaptic contacts with dendrites Injection of antisense oligonucleotide to sPLA2-XIIA in the PFC resulted in increases in phospholipid but decreases in lysophospholipid molecular species, consistent with decreased catalytic activity of the enzyme, and alterations in sphingolipids sPLA2-XIIA knockdown also resulted in shorter latency timings in the passive avoidance test, and higher number of errors in the attention set-shifting task, indicating deficits in working memory and attention, respectively Together the results show an important role of sPLA2-XIIA in lipid metabolism and cognition We postulate that sPLA2-XIIA may induce remodeling VII Summary 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Expression Profile of various PLA2 isoforms in the CNS CHAPTER EXPRESSION PROFILE OF VARIOUS PLA2 ISOFORMS IN THE CNS 29 Chapter Expression Profile of various PLA2 isoforms in the CNS 2.1.1 Introduction... hippocampus including CA1-3 fields, dentate gyrus and brainstem (Shirai and Ito, 2004) The significance of PLA2 in maintaining membrane lipid homeostasis of the brain is evident in all these studies