The role of hydrogen sulfide in the central nervous system implications in the treatment of alzheimers disease

THE ROLE OF HYDROGEN SULFIDE IN THE CENTRAL NERVOUS SYSTEM: IMPLICATIONS IN TREATMENT OF ALZHEIMER’S DISEASE BHUSHAN VIJAY NAGPURE NATIONAL UNIVERSITY OF SINGAPORE 2014 THE ROLE OF HYDROGEN SULFIDE IN THE CENTRAL NERVOUS SYSTEM: IMPLICATIONS IN TREATMENT OF ALZHEIMER’S DISEASE BHUSHAN VIJAY NAGPURE (M.B.B.S., Maharashtra University of Health Sciences, India) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2014 DECLARATION I hereby declare that this thesis is my original work and it has been written by me in its entirety I have duly acknowledged all the sources of information that have been used in the thesis This thesis has also not been submitted for any degree in any university previously Bhushan Vijay Nagpure 21st July 2014 I       ACKNOWEDGEMENTS First of all, I would like to express my deepest gratitude to my supervisor, A/P Bian Jinsong, for providing me the opportunity to continue with my graduate studies I appreciate his scientific advices during the course of study I also want to thank him for his support and encouragement throughout my journey of PhD Sincere appreciation to the lab technologist, Ms Shoon Mei Leng, for assisting with laboratory matters Many thanks to my fellow past and present colleagues at A/P Bian Jinsong’s laboratory, Wu Zhiyuan, Hua Fei, Cao Xu, Xie Li, Tiong Chi Xin, Li Guang, Liu Yanying, Liu Yitong, Lu Ming and Hu Lifang for their insightful discussion, technical advice and help in one way or another I would also extend my gratitude to Yong Loo Lin School of Medicine, National University of Singapore for offering me scholarship and providing me the opportunity to pursue higher studies in Singapore Finally, I would also like to convey my greatest gratitude to my parents, my brother and my wife for their continuous love, encouragement and support in past few years II       TABLE OF CONTENTS ACKNOWEDGEMENTS II TABLE OF CONTENTS III SUMMARY VII LIST OF TABLES X LIST OF FIGURES XI LIST OF ABBREVEATIONS XII LIST OF PUBLICATIONS XIV Introduction and Literature Review 1.1 The trio of gasotransmitters 1.1.1 H2S- The ‘third’ gasotransmitter 1.1.1.1 Physical and chemical properties of H2S 1.1.1.2 Toxicity of H2S 1.1.1.3 Biosynthesis of H2S 1.1.1.4 Storage and metabolism of H2S 1.1.1.5 Biological role of H2S in CNS 1.2 Alzheimer’s disease 16 1.2.1 History 16 1.2.2 Epidemiology 17 1.2.3 Risk factors 19 1.2.4 Pathology 20 1.2.4.1 Amyloid β 20 1.2.4.2 Tau 21 1.2.4.3 Studies done on animal models and AD patients 22 1.2.4.4 Other etiopathological hypotheses 23 1.2.5 ATP and its metabolites in AD 26 1.2.6 Diagnosis and clinical symptoms of AD 28 1.2.6.1 Classification and Diagnostic criteria 28 1.2.6.2 Clinical symptoms and the course of the illness 29 1.2.7 Pharmacotherapy 31 1.3 Objectives 34 Materials and methods 36 2.1 Chemicals 37 2.2 Cell Culture and Treatments 37 2.3 Constructs and Mutagenesis 39 III       2.4 Preparation of Primary Astrocyte Culture 40 2.5 Cell Viability Assay 40 2.6 Intracellular cAMP Assay 41 2.7 Cell Fractionation and Adenylyl Cyclase (AC) Activity Assay 41 2.8 γ-secretase (Fluorogenic Substrate) Assay 42 2.9 ELISA for Aβ42 42 2.10 Reactive Oxygen Species (ROS) Measurement 43 2.11 Measurement of Nitric Oxide 43 2.12 ELISA for TNF-α and IL-Iβ 43 2.13 DNA binding activity assay 43 2.14 Cathepsin S activity assay 44 2.15 S-sulfhydration assay (modified biotin switch) 44 2.16 Glutamate uptake assay 45 2.17 Reverse Transcription-PCR 45 2.18 Western Blot Assay 47 2.19 Statistical Analysis 47 Hydrogen sulfide inhibits A2A adenosine receptor agonist induced βamyloid production in SH-SY5Y neuroblastoma cells via a cAMP dependent pathway 49 3.1 Introduction 50 3.2 Materials and Methods 52 3.2.1 Chemicals 52 3.2.2 Cell Culture and Treatments 52 3.2.3 Cell Viability Assay 52 3.2.4 Intracellular cAMP Assay 52 3.2.5 Cell Fractionation and Adenylyl Cyclase (AC) Activity Assay 52 3.2.6 γ-secretase (Fluorogenic Substrate) Assay 52 3.2.7 ELISA for Aβ42 52 3.2.8 Reverse Transcription-PCR 52 3.2.9 Western Blot Assay 52 3.2.10 Statistical Analysis 53 3.3 Results 53 3.3.1 NaHS attenuates adenosine A2A receptor agonist stimulated Aβ42 production 53 3.3.2 The involvement of cAMP/PKA/CREB pathway in the inhibitory effect of NaHS on HENECA-stimulated Aβ42 production 56 IV       3.3.3 3.3.4 3.3.5 3.3.6 3.4 NaHS targets activated AC, not A2A receptors 59 NaHS inhibits APP production and maturation 62 NaHS attenuates γ–secretase activity, not of β–secretase 64 Effect of NaHS on expression of presenilins 67 Discussion 68 Hydrogen sulfide repairs impaired glutamate uptake in A2A adenosine receptor agonist-stimulated primary astrocytes 77 4.1 Introduction 78 4.2 Material and Methods 79 4.2.1 Chemicals 79 4.2.2 Primary astrocyte culture 80 4.2.3 Intracellular cAMP Assay 80 4.2.4 Glutamate uptake assay 80 4.2.5 Statistical analysis 80 4.3 Results 80 4.3.1 The effect of NaHS on glutamate uptake in A2A adenosine receptor agonist stimulated astrocytes 81 4.3.2 The involvement of cAMP signaling pathway in the protective effect of NaHS on HENECA-stimulated astrocytes 82 4.4 Discussion 83 Hydrogen sulfide inhibits the Aβ synthesis and neuroinflammation in extracellular ATP-stimulated BV-2 microglia cells via inhibition of NF-κB , STAT3 and cathepsin S activation 86 5.1 Introduction 87 5.2 Materials and Methods 90 5.2.1 Chemicals 90 5.2.2 Cell Culture and Treatments 90 5.2.3 Constructs and mutagenesis 90 5.2.4 Cell Viability Assay 90 5.2.5 Intracellular cAMP Assay 90 5.2.6 γ-secretase (Fluorogenic Substrate) Assay 90 5.2.7 ELISA for Aβ42 90 5.2.8 Reactive Oxygen Species (ROS) Measurement 90 5.2.9 Nitric oxide (NO) Measurement 90 5.2.10 DNA binding activity assay 91 5.2.11 Cathepsin S activity assay 91 5.2.12 S-sulfhydration assay 91 5.2.13 Western Blot Assay 91 5.2.14 Statistical Analysis 91 5.3 Results 91 V       5.3.1 Effect of NaHS on ATP-induced oxidative stress and inflammation in BV-2 microglial cells 91 5.3.2 Effect of NaHS on ATP-induced iNOS and COX-2 expression in microglial cells 94 5.3.3 Effect of NaHS on DNA binding and transcriptional activities of NF-κB in ATP-stimulated microglial cells 96 5.3.4 Effect of NaHS on ATP-induced Aβ42 production in microglial cells 98 5.3.5 Effect of NaHS on STAT3 activity in microglial cells 101 5.3.6 Involvement of cathepsin S in the observed effects of NaHS on ATP-induced neuroinflammation and Aβ production 103 5.4 Discussion 107 General Discussion, Limitations of study, Future directions and Conclusion 113 Bibliography 120   VI       SUMMARY In today’s world, Alzheimer’s disease (AD) is the leading cause of dementia in elderly population across the world It is also the most common neurodegenerative disease With high prevalence and ever growing incidence rate, AD is set to become one of the most crippling diseases in developed and developing countries Currently, only few approved drugs are available for the treatment of AD Majority of them are prescribed to alleviate neuropsychiatric symptoms without targeting underlying pathological mechanism Hence, a lot of efforts have been put into the development of disease-modifying drug therapy Amyloidogenesis is one of the main culprits of AD pathology The effect of NaHS, a rapid exogenous hydrogen sulfide (H2S) donor, was first examined in SH-SY5Y cells transfected with amyloid precursor protein (APP) Swedish mutation H2S pretreatment was found to exert an inhibitory effect on Aβ42 synthesis by HENECA (a selective A2A receptor agonist)-stimulated SH-SY5Y cells NaHS also interfered with the maturation process of APP by inhibiting its generation and post-translational modification A further study of the rate limiting steps of Aβ synthesis i.e β- and γ-secretase activities yielded interesting results H2S did not affect the β-secretase activity However, γsecretase activity measurement and gene expression study of presenilins revealed that H2S directly inhibited γ-secretase Curiously, H2S also abrogated intracellular cAMP levels and phosphorylation of downstream CREB H2S had similar suppressive effects on cAMP and Aβ42 generation caused by specific AC stimulation A further study showed that HENECA-stimulated AC activity VII       and gene expression of AC isoforms were preferentially blocked by H2S while exerting its inhibitory action on Aβ synthesis A2A adenosine receptors are known to modulate glutamate uptake in astroglial cells When incubated with HENECA, protein expression of GLAST glutamate transporter and glutamate uptake were significantly inhibited in astrocytes The pretreatment with NaHS significantly improved the impaired glutamate uptake and expression of GLAST glutamate transporter Being positively linked to AC, stimulation of A2A receptors by HENECA resulted into the increase in intracellular cAMP levels Similar to the first part of the studies, NaHS inhibited the cAMP production in astrocytes These data suggest that H2S -inhibited cAMP production was probably responsible for its regenerative effect on glutamate uptake and restoration of GLAST Several line of evidences show that severe neuroinflammation leads to amyloidogenesis in the CNS By the detailed analysis of generation of many inflammatory parameters, it was found that H2S pretreatment suppressed extracellular ATP-induced severe neuroinflammation in immortalized BV-2 cells While exerting its anti-inflammatory effect, H2S also imparted the inhibitory effect on Aβ synthesis in microglia NF-κB and STAT3 are responsible for transcription of many inflammatory genes The activation of both the transcription factors was blocked by H2S Cathepsin S, which was found to be situated downstream to STAT3 in the current study, was involved in β-secretase cleavage of APP and NF-κB activation We found that H2S ssulfhydrated Cathepsin S and inhibited its expression and activity in ATPstimulated BV-2 cells VIII       EXLEY, C & KORCHAZHKINA, O V 2001 Promotion of formation of amyloid fibrils by 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Curr Med Chem, 17, 213-21 138       .. .THE ROLE OF HYDROGEN SULFIDE IN THE CENTRAL NERVOUS SYSTEM: IMPLICATIONS IN TREATMENT OF ALZHEIMER’S DISEASE BHUSHAN VIJAY NAGPURE (M.B.B.S., Maharashtra University of Health Sciences, India)... lot of efforts have been put into the development of disease- modifying drug therapy Amyloidogenesis is one of the main culprits of AD pathology The effect of NaHS, a rapid exogenous hydrogen sulfide. .. like tau is involved in microtubule assembly It serves as a binding for the tubulin Mutations in α-synuclein lead to loss of this binding ability, resulting in tubulin and α-synuclein aggregation