Possible role of diva in microglial dual effects and the stem cell differentiation

POSSIBLE ROLE OF DIVA IN MICROGLIAL DUAL EFFECTS AND THE STEM CELL DIFFERENTIATION LI LV (B.Sc) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF ANATOMY YONG LOO LIN SCHOOL OF MEDICINE NATIONAL UNIVERSITY OF SINGAPORE 2007 ii ACKNOWLEDGMENTS I would like to express my deepest appreciation to my three supervisors, Assistant Professor He Beiping, Associate Professor Lu Jia and Associate Professor Samuel Sam Wah Tay, Department of Anatomy, National University of Singapore, for their innovative ideas, invaluable guidance, constant encouragement, infinite patience, and friendly critics throughout this study Without them, this dissertation would never be completed I am very grateful to Professor Ling Eng Ang, Head of Anatomy Department, National University of Singapore, for his constant support and encouragement to me, and also for his full support in using the excellent research facilities I must also acknowledge my gratitude to Mrs Yong Eng Siang, Mrs Ng Geok Lan, Mrs Cao Qiong, Ms Chan Yee Gek and the late Miss Margaret Sim for their excellent technical assistance; Mr Yick Tuck Yong, Mr Low Chun Peng and Ms Bay Song Lin for their constant assistance in computer work; Mr Lim Beng Hock for looking after the experimental animals; and Mdm Ang Lye Gek Carolyne, Mdm Diljit Kaur, Mdm Teo Li Ching Violet for their secretarial assistance I would like to express my special thanks to Associate Professor Shabbir M Moochhala, Ms Tan Mui Hong, Ms Tan Li Li and Ms Clara Lim, DEMRI, DSO National Laboratories, their continuous help, support and advice when I did my project in DSO National Laboratories iii I would like to thank all other staff members and my fellow postgraduate students at Department of Anatomy, National University of Singapore for their help and support I would like to take this opportunity to express my heartfelt thanks to my parents for their full and endless support for my study iv This thesis is dedicated to my beloved family v PUBLICATIONS International Journals: 1: Li L, Lu J, Tay SS, Moochhala SM, He BP The function of microglia, either neuroprotection or neurotoxicity, is determined by the equilibrium among factors released from activated microglia in vitro Brain Res 2007 Jul 23;1159:8-17 2: Li L, Lu J, Tay SS, Moochhala SM, He BP Diva plays a protective role in NSC-34 cells under microglia cytotoxicity and promote the proliferation of NSC-34 cells in vitro (In preparation) 3: Li L, Lu J, Tay SS, Moochhala SM, He BP The possible role of Diva during neural stem cells differentiation (In preparation) Conference papers: 1: Li L, Tay SSW, Lu J, Moochhala S, He BP The Effects of LPS-activated BV-2 Conditioned Medium on The NSC-34 Cells, Protective or Toxic? The 16th International Microscopy Congress 2006 3rd-8th September, 2006 Sapporo, Japan 2: Li L, Tay SSW, Lu J, Moochhala S, He BP LPS-activated BV- conditioned media cause the translocation of Diva from cytosol to mitochondria 6th National Symposium on Health Sciences 2006 6th-7th June, 2006, Kuala Lumpur, Malaysia 3: Li Lv, Tay SSW, Lu J, Moochhala S, He BP Protective effects of LPS-activated BV-2 conditioned medium on the formation of aggregates in NSC-34 cells ChinaSingapore Biomedical Science Conference 3rd-7th, December, 2004, Kunming, Yunnan, China 4: Li Lv, Tay SSW, Lu J, Moochhala S, He BP Aggregate-bearing motor neurons are more vulnerable to microglial toxicity 8th NUS-NUH Annual Science Meeting, 2nd-3rd October, 2004, Singapore vi TABLE OF CONTENTS ACKNOWLEDGEMENTS…………………………………………………………… ii DEDICATIONS…………………………………………………………………………iv PUBLICATIONS……………………………………………………………………… v TABLE OF CONTENTS……………………………………………………………….vi ABBREVIATIONS…………………………………………………………………….xiv SUMMARY……………………………………………………………………………xvii CHAPTER INTRODUCTION……………………………………………………… 1 Microglia in the central nervous system……………………………………………… 2 Molecular aspects of microglia…………………………………………………………2 Microglia in neurodegenerative diseases……………………………………………….4 Dual functions of microglia…………………… …………………………………… 4.1 Microglial neuroprotective function…………………………………………… 4.2 Microglial cytotoxicity………………………………………………………… 4.3 Microglial dual-function: when and why……………………………………… Apoptosis and neuron death………………………………………………….……… 10 5.1 Apoptosis……………………………………………………………….……….10 5.2 Necrosis……………………………………………………………………… 10 5.3 Involvement of apoptosis in neurological diseases…………………………… 11 5.4 Microglial cytotoxicity induced apoptosis…………………………………… 11 5.5 Caspases and two apoptosis pathways.……………………………… ………12 5.5.1 Death-receptor activated apoptosis……………………………………….12 vii 5.5.2 Mitochondria-mediated apoptosis……………………………….……… 13 5.6 Key regulators of mitochondrial apoptosis………………………….………….14 5.6.1 Bcl-2 family …………………………………………………………… 14 5.6.2 Bcl-2 family members in neuron death………………………………… 15 5.6.3 Diva, a new identified Bcl-2 family member…………………………… 16 5.6.3.1 Structure of Diva……………………………………………… 17 5.6.3.2 Distribution of Diva in vivo…………………………………….17 5.6.3.3 Function of Diva in apoptosis………………………………… 18 5.6.4 Bcl-2 family members in cell cycle……………………………………….19 Cell cycle and stem cell differentiation……………………………………………….20 6.1 Neural stem cells……………………………………………………………… 20 6.1.1 Neural stem cells in vivo and in vitro………………………………… …21 6.1.2 Bcl-2 family members and neural stem cells…………………………… 22 Hypothesis……………………………………………………………………………22 Aims and scopes…………………………………………………………………… 24 8.1 To identify the possible relationship between microglia activation and its dual function in vitro……………………………………………………………….24 8.2 To verify microglial protective or destructive function in protein aggregatecontaining neuron model in vitro…………………………………………… 24 8.3 To identify the possible involvement of Bcl-2 family members in neurons during the interaction between microglia and neurons……………………………….25 8.4 To study Diva in animal and cell models ………………………………………25 8.4.1 To investigate the distribution of Diva in the CNS……………………….25 viii 8.4.2 To evaluate the possible role of Diva in response to microglial cytotoxicity ………………………………………………………………………………….25 8.4.3 To evaluate the possible role of Diva during the cell cycle regulation in both NSC-34 and neural stem cells…………………………………….26 CHAPTER EXPERIMENTAL STUDIES,……………………………………….27 I: Determination of Microglial Dual Function by the Concentrations of Factors Released from Activated Microglia in vitro…………………………………………28 Introduction………………………………………………………………………….29 Materials and methods………………………………………………………………31 2.1 Tissue cell culture……… ……………………………….………………… 31 2.2 Activation of BV-2 cells by Lipopolysaccharide…………………………… 32 2.3 Investigation of pro-inflammatory factors by ELISA assay ………………… 32 2.4 Treatment of NSC-34 cells with LPS-BVCM and LPS……………………… 33 2.5 MTS assay…………………………………………………………………… 34 2.6 Apoptosis assays……………………………………………………………….35 2.7 Induction of aggregates in NSC-34 neurons………………………………… 36 2.8 Detection of aggregates by immunohistochemistry………………………… 36 2.9 Effects of 1μg/ml LPS-BVCM on the formation of aggregates in NSC-34 neurons …………………………………………………………………………………… 38 2.10 Neurite growth assay………………………………………………………….38 2.11 Statistical analysis…………………………………………………………….39 Results……………………………………………………………………………….39 ix 3.1 Quantification of TNF-α, IL-1β and IL-6 in LPS-BVCM by ELISA………….39 3.2 Effects of LPS stimulated BV-2 conditioned medium (LPS-BVCM) on the NSC34 cell viability…………………………………………………… ………….40 3.3 PS externalization in NSC-34 cells ……………………………………… ……43 3.4 The effects of 2,5-HD on NSC-34 neurons……………………………… ……44 3.5 Effects of LPS-BVCM on the formation of aggregates in NSC-34 cells….… 47 3.6 Effects of LPS-BVCM on the outgrowth of processes of NSC-34 neurons ……………………………………………………………………… …………48 Discussion……………………………………………………………… ………… 50 4.1 The nature of microglial function could be determined by the amount of LPS applied to microglia…………………………………………………… ……….50 4.2 The concentration of conditioned medium from 1μg/ml LPS-stimulated microglia present opposing functions: neuroprotection or neurotoxicity……… …………51 4.3 Lower concentration of LPS-activated microglia conditioned medium can prevent the formation of protein aggregation in neurons from 2,5-HD toxicity……… 52 4.4 Lower concentration of LPS-activated microglia conditioned medium can promote the outgrowth of the processes of neurons………………… …………52 4.5 Mechanism of microglial dual effects: Equilibrium in functions of various biofactors released from activated microglia is the key in microglial dual function ………………………………………………………………………………….53 II: Possible Role of Diva in the Interaction between BV-2 and NSC-34 Cells…….56 Introduction………………………………………………………………………… 57 x Materials and methods……………………………………………………………… 59 2.1 Tissue cell culture……………………………………………………………….59 2.2 Activation of BV-2 cells by Lipopolysaccharide (LPS)…………….………… 60 2.3 Treatment of NSC-34 cells by LPS-BVCM………………………… …………60 2.4 Real-Time polymerase chain reaction (Real-Time PCR)………… ……………60 2.5 Detection of real-time RT-PCR products specificities…………… ……………63 2.6 Overexpression of Diva in NSC34 cells………………………….……….…… 63 2.7 Transfection of pcDNA6-Diva into NSC-34 cells……………….…………… 69 2.8 Immunocytochemistry………………………………………… ……………….71 Results………………………………………………………………… …………… 74 3.1 Expression of Bcl-2 family members in NSC-34 cells after being treated with different concentrations of LPS-BVCM………………………………… …… 74 3.2 Immunostaining of Diva after treated with 25% LPS-BVCM in NSC-34 cells …………………………………………………………………………… …… 79 3.3 Construction of Overexpression Plasmid for Diva……………………….…… 81 3.4 Overexpression of pcDNA6-Diva in NSC-34 cells………………….………… 84 3.5 Proliferation assay of NSC-34 cells after 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