Disease-Modifying Targets in Neurodegenerative Disorders : Paving the Way for Disease-Modifying Therapies

__Disease-Modifying Targets in Neurodegenerative Disorders: Paving the Way for Disease-Modifying Therapies__ examines specific neurodegenerative disorders in comprehensive chapters written by experts in the respective fields. Each chapter contains a summary of the disease management field, subsequently elaborating on the molecular mechanisms and promising new targets for disease-modifying therapies. This overview is ideal for neuroscientists, biomedical researchers, medical doctors, and caregivers, not only providing readers with a summary of the way patients are treated today, but also offering a glance at the future of neurodegenerative disorder treatment. Disease-Modifying Targets in Neurodegenerative Disorders, (2017) 320pp. 978-0-12-805120-7 Cover 1 Title Page 4 Copyright Page 5 Contents 6 List of Contributors 12 Editor Biographies 14 Foreword 15 Preface 17 Chapter 1 - The multitude of therapeutic targets in neurodegenerative proteinopathies 18 Protein Misfolding and Aggregation 18 Mechanism of Assembly 19 Prion-Like Propagation of Protein Assemblies 21 Propagation Routes of Pathogenic Protein Aggregates 22 Limiting Steps in the Propagation of Pathogenic Protein Assemblies 23 Therapeutic Strategies Targeting the Physiological Levels of Aggregation-Prone Proteins Involved in Neurodegeneration 24 Therapeutic Strategies Targeting the Misfolding and Aggregation of Proteins Involved in Neurodegeneration 24 Therapeutic Strategies Targeting the Accumulation of Misfolded Pathologic Protein Aggregates 25 Therapeutic Strategies Targeting the Cell-to-Cell Propagation of Pathogenic Protein Aggregates 26 Therapeutic Strategies Aimed at Restoring the Damage Pathogenic Protein Aggregates Induce 26 Therapeutic Strategies Targeting Misfolded Pathologic Protein Aggregate–Mediated Neuroinflammation 27 Limitations of the Different Therapeutic Strategies 28 Acknowledgments 29 References 29 Chapter 2 - Synuclein misfolding as a therapeutic target 38 Introduction 38 The Conformational Landscape of α-Synuclein: the Native State 39 Cytosolic Folding States 41 Membrane-Bound Folding States 41 The Conformational Landscape of α-Synuclein: Misfolded Variants 42 Folding Intermediates 42 Oligomeric Variants 44 Fibrillar Variants 46 Misfolding in Complex Environments 47 Synuclein Strains 49 Glycation of α-SYN—an Age-Associated Posttranslational Modification 49 Misfolding of α-Synuclein as a Therapeutic Target 50 Preserving the Native State 50 Preventing the Formation of Folding Intermediates 50 Targeting Aggregation 52 Lowering α-synuclein expression levels 52 Direct inhibition of α-synuclein aggregation 53 Stabilizing Membrane Interactions 55 Conclusions 55 References 56 Chapter 3 - Neuroinflammation as a therapeutic target in neurodegenerative diseases 66 Introduction 67 The Global Burden of Neurodegenerative Diseases and the Challenge of Developing Effective Therapeutics 67 Glial Cells in CNS Development, Homeostasis, and Pathology 68 Microglia 68 Astrocytes 70 Oligodendrocytes and Ependymal Cells 71 Chronic Neuroinflammation as a Common Pathophysiological Mediator in Progressive Neurodegenerative Diseases 71 Mechanisms of Neuroinflammation-Mediated Neurodegeneration 73 Alzheimer’s Disease 75 Parkinson’s Disease 77 Amyotrophic Lateral Sclerosis 81 Huntington’s Disease 82 Frontotemporal Dementia and Lewy Body Dementia 83 Therapeutic Strategies Targeting Neuroinflammation in Progressive Neurodegenerative Diseases 83 Future Perspectives 86 Conclusions 87 References 87 Chapter 4A - Stem cells in neurodegeneration: mind the gap 98 Introduction 98 Part I: Stem Cells 99 Genome Editing of Stem Cells 100 The Generation of Specific Cell Types 101 Part II: Stem Cells as Regenerative Therapy 102 Clinical Translation and Immunology 105 Keeping Track of Cell Transplants 107 Part III: Stem Cells to Model Neurodegenerative Diseases 108 iPSC Characteristics: The Role of Development in Neurodegenerative Diseases 108 iPSC Technology: Disease Modeling and Drug Screening 109 Amyotrophic lateral sclerosis 110 Alzheimer’s disease 112 Parkinson’s disease 112 Future Prospects 113 References 113 Chapter 4B - The potential of stem cells in tackling neurodegenerative diseases 118 Endogenous Stem Cells as a Therapeutic Target 118 What are Endogenous Stem Cells? 118 The mechanism of adult neurogenesis 118 The subventricular zone 118 The dentate gyrus 119 Stem cell niche modulation 120 Human relevance 120 The subventricular zone 120 The dentate gyrus 121 Adult Neurogenesis in a Neurodegenerative Environment 121 Parkinson’s disease 121 Acute lesion models 121 Transgenic animal models 122 Human patients 122 Alzheimer’s disease 123 Transgenic animal models 123 Human patients 123 Huntington’s disease 124 Animal models 124 Patients 124 Summary 124 Adult Brain Regeneration to Tackle Neurodegeneration 125 Increasing the endogenous pool of stem cells 125 Environmental enrichment 125 Pharmaco- and gene therapy 125 Cell transplantation 126 As a model system 126 Summary 126 References 127 Chapter 5 - Preclinical models of Alzheimer’s disease for identification and preclinical validation of therapeutic targets: From fine-tuning strategies for validated targets to new venues for therapy 132 Introduction 133 Alzheimer’s Disease: Clinical Features, Pathology, and Genetics Leading to the Formulation of the Amyloid Cascade Hypothesis 133 Clinical features 133 Neuropathology 133 Genetics 134 The amyloid cascade hypothesis 135 Transgenic Models Recapitulating Amyloid Pathology as Preclinical Models to Identify Targets for Anti-Aβ Therapies 135 APP and APP/PS1 transgenic models 135 Secretases and their validation as therapeutic targets 136 Clearance of Aβ by immunotherapy 138 Identification of the exact toxic form(s) of Aβ and aggregation inhibitors 139 Combination of different anti-Aβ strategies and other approaches 140 Limitations of APP and APP/PS1 preclinical models 140 Transgenic Models Recapitulating Tau-Pathology as Preclinical Models to Identify Targets for Anti-Tau-Directed Therapies 141 Tau-transgenic models recapitulating tau-pathology 141 Targeting tau-phosphorylation and other posttranslational modifications of tau 143 Microtubule-stabilizing agents 143 Targeting intracellular tau-degradation 144 Targeting tau by immunization therapy 144 Transgenic Mouse Models Recapitulating Prion-Like Spreading and Propagation of Tau-Pathology: New Venues for Therapeutic Strategies 145 Demonstration of prion-like spreading of tau-pathology in preclinical tauopathy models in vivo: proof of concept 146 Targeting extracellular release and uptake of misfolded tau, acting as tau-seeds for prion-like propagation of tau-pathology 146 Immunotherapy targeting extracellular misfolded forms of tau to inhibit prion-like propagation of tau-pathology 148 Targeting tau-misfolding and aggregation to inhibit prion-like propagation of tau-pathology 149 Transgenic Mouse Models Recapitulating Aβ-to-Tau Axis: New Venues to Identify Novel Therapeutic Targets Aiming at the Molecular and cellular mechanisms linking aβ and tau 149 Animal models of AD robustly recapitulate Aβ-induced tau-pathology 149 Molecular and cellular mechanisms of Aβ-induced tau-pathology 150 Neuronal signaling pathways downstream of Aβ as a potential mechanism of Aβ-induced tau-pathology 150 Aβ-induced inflammation as a potential mechanism of Aβ-induced tau-pathology 152 Heterotypic seeding of tau-aggregation by preaggregated Aβ as a potential mechanism of Aβ-induced tau-pathology 153 Conclusions 154 References 155 Chapter 6 - Parkinson’s disease 174 Introduction 174 Current Treatment Approaches in Parkinson’s Disease 175 Pharmacological Approaches: Replacing Dopamine 175 Nonpharmacological Approaches: Deep Brain Stimulation and Cell Replacement 177 Drugs That are Being Evaluated Clinically for Disease Modification in PD 177 Novel Targets for Disease-Modifying Therapies in PD 178 α-Synuclein 178 Is there a toxic species characterized by form or localization? 180 Reducing the total amount of α-synuclein 181 LRRK2 182 Recessive Genes 183 Conclusions 184 Acknowledgments 184 References 185 Chapter 7 - Lewy body dementia 192 Lewy Body Dementia 192 Concept of Lewy Body Dementia 192 Clinical Symptoms 194 Genetic Association 194 Pathophysiology 195 Alpha-synuclein 195 Tau and amyloid 198 Chaperones proteins 198 Neuroinflammation 198 Management of LBD 199 Current Symptomatic Treatment 199 Disease-Modifying Therapy 200 Targeting αsyn protein 200 Clearance of αsyn 200 Modulating αsyn oligomerization 201 Extracellular αsyn and it propagation 202 Modulation of αsyn aggregation by chaperones proteins 203 Deep brain stimulation 204 Concluding Remarks 205 References 205 Chapter 8 - Frontotemporal dementia 216 Overview of Frontotemporal Dementia 216 Clinical Presentations 217 Pathological Heterogeneity 218 Genetics of FTD 219 Causal genes 219 Disease risk 221 FTD: A Heterogeneous Disorder 222 Disease Management 223 Pharmacologic Symptomatic Treatment 223 Behavioral and cognitive symptoms 223 Aphasia 225 Motor symptom management 225 Nonpharmacologic Management 226 Novel Possibilities in Disease-Modifying Drug Development 226 Tau 226 Granulin 231 C9orf72 233 TDP-43 236 Cellular Waste Clearance Systems 237 Heterogeneity = Opportunity 239 Discussion: Essentials for the Development of a Disease-Modifying Therapy 241 Gaps in our Understanding of FTD 241 Toward Early and Targeted Intervention 243 Conclusions 244 References 244 Chapter 9 - From huntingtin gene to Huntington’s disease-altering strategies 268 Huntington’s Disease 268 Huntingtin Gene and Transcripts 270 Huntingtin Protein 274 HD Pathogenic Mechanisms 275 Molecular Strategies for HD 276 ASO 277 RNA Interference 278 Genome Editing 279 Conclusions and Perspectives 280 Acknowledgments 281 References 281 Chapter 10 - Amyotrophic lateral sclerosis: mechanisms and therapeutic strategies 294 Introduction 294 Excitotoxicity 297 Hyperexcitability 298 Pathogenic Role of Non-Neuronal Cells 298 Astrocyte Dysfunction 298 Oligodendrocyte Dysfunction 299 Microglial Dysfunction and T Cells 299 Shortage of Neurotrophic Factors 300 Mitochondrial Dysfunction 301 Axonal Defects 301 Altered Proteostasis and Autophagy 302 Altered RNA Metabolism and Stress Granule Formation 303 Hexanucleotide Repeats in C9ORF72 and Disturbances in Nucleocytoplasmic Transport 303 Conclusions 304 Acknowledgments 305 References 305 Index 314 Back cover 324 Cover......Page 1 Title Page......Page 4 Copyright Page......Page 5 Contents......Page 6 List of Contributors......Page 12 Editor Biographies......Page 14 Foreword......Page 15 Preface......Page 17 Protein Misfolding and Aggregation......Page 18 Mechanism of Assembly......Page 19 Prion-Like Propagation of Protein Assemblies......Page 21 Propagation Routes of Pathogenic Protein Aggregates......Page 22 Limiting Steps in the Propagation of Pathogenic Protein Assemblies......Page 23 Therapeutic Strategies Targeting the Misfolding and Aggregation of Proteins Involved in Neurodegeneration......Page 24 Therapeutic Strategies Targeting the Accumulation of Misfolded Pathologic Protein Aggregates......Page 25 Therapeutic Strategies Aimed at Restoring the Damage Pathogenic Protein Aggregates Induce......Page 26 Therapeutic Strategies Targeting Misfolded Pathologic Protein Aggregate–Mediated Neuroinflammation......Page 27 Limitations of the Different Therapeutic Strategies......Page 28 References......Page 29 Introduction......Page 38 The Conformational Landscape of α-Synuclein: the Native State......Page 39 Membrane-Bound Folding States......Page 41 Folding Intermediates......Page 42 Oligomeric Variants......Page 44 Fibrillar Variants......Page 46 Misfolding in Complex Environments......Page 47 Glycation of α-SYN—an Age-Associated Posttranslational Modification......Page 49 Preventing the Formation of Folding Intermediates......Page 50 Lowering α-synuclein expression levels......Page 52 Direct inhibition of α-synuclein aggregation......Page 53 Conclusions......Page 55 References......Page 56 Chapter 3 - Neuroinflammation as a therapeutic target in neurodegenerative diseases......Page 66 The Global Burden of Neurodegenerative Diseases and the Challenge of Developing Effective Therapeutics......Page 67 Microglia......Page 68 Astrocytes......Page 70 Chronic Neuroinflammation as a Common Pathophysiological Mediator in Progressive Neurodegenerative Diseases......Page 71 Mechanisms of Neuroinflammation-Mediated Neurodegeneration......Page 73 Alzheimer’s Disease......Page 75 Parkinson’s Disease......Page 77 Amyotrophic Lateral Sclerosis......Page 81 Huntington’s Disease......Page 82 Therapeutic Strategies Targeting Neuroinflammation in Progressive Neurodegenerative Diseases......Page 83 Future Perspectives......Page 86 References......Page 87 Introduction......Page 98 Part I: Stem Cells......Page 99 Genome Editing of Stem Cells......Page 100 The Generation of Specific Cell Types......Page 101 Part II: Stem Cells as Regenerative Therapy......Page 102 Clinical Translation and Immunology......Page 105 Keeping Track of Cell Transplants......Page 107 iPSC Characteristics: The Role of Development in Neurodegenerative Diseases......Page 108 iPSC Technology: Disease Modeling and Drug Screening......Page 109 Amyotrophic lateral sclerosis......Page 110 Parkinson’s disease......Page 112 References......Page 113 The subventricular zone......Page 118 The dentate gyrus......Page 119 The subventricular zone......Page 120 Acute lesion models......Page 121 Human patients......Page 122 Human patients......Page 123 Summary......Page 124 Pharmaco- and gene therapy......Page 125 Summary......Page 126 References......Page 127 Chapter 5 - Preclinical models of Alzheimer’s disease for identification and preclinical validation of therapeutic targets: From fine-tuning strategies for validated targets to new venues for therapy......Page 132 Neuropathology......Page 133 Genetics......Page 134 APP and APP/PS1 transgenic models......Page 135 Secretases and their validation as therapeutic targets......Page 136 Clearance of Aβ by immunotherapy......Page 138 Identification of the exact toxic form(s) of Aβ and aggregation inhibitors......Page 139 Limitations of APP and APP/PS1 preclinical models......Page 140 Tau-transgenic models recapitulating tau-pathology......Page 141 Microtubule-stabilizing agents......Page 143 Targeting tau by immunization therapy......Page 144 Transgenic Mouse Models Recapitulating Prion-Like Spreading and Propagation of Tau-Pathology: New Venues for Therapeutic Strategies......Page 145 Targeting extracellular release and uptake of misfolded tau, acting as tau-seeds for prion-like propagation of tau-pathology......Page 146 Immunotherapy targeting extracellular misfolded forms of tau to inhibit prion-like propagation of tau-pathology......Page 148 Animal models of AD robustly recapitulate Aβ-induced tau-pathology......Page 149 Neuronal signaling pathways downstream of Aβ as a potential mechanism of Aβ-induced tau-pathology......Page 150 Aβ-induced inflammation as a potential mechanism of Aβ-induced tau-pathology......Page 152 Heterotypic seeding of tau-aggregation by preaggregated Aβ as a potential mechanism of Aβ-induced tau-pathology......Page 153 Conclusions......Page 154 References......Page 155 Introduction......Page 174 Pharmacological Approaches: Replacing Dopamine......Page 175 Drugs That are Being Evaluated Clinically for Disease Modification in PD......Page 177 α-Synuclein......Page 178 Is there a toxic species characterized by form or localization?......Page 180 Reducing the total amount of α-synuclein......Page 181 LRRK2......Page 182 Recessive Genes......Page 183 Acknowledgments......Page 184 References......Page 185 Concept of Lewy Body Dementia......Page 192 Genetic Association......Page 194 Alpha-synuclein......Page 195 Neuroinflammation......Page 198 Current Symptomatic Treatment......Page 199 Clearance of αsyn......Page 200 Modulating αsyn oligomerization......Page 201 Extracellular αsyn and it propagation......Page 202 Modulation of αsyn aggregation by chaperones proteins......Page 203 Deep brain stimulation......Page 204 References......Page 205 Overview of Frontotemporal Dementia......Page 216 Clinical Presentations......Page 217 Pathological Heterogeneity......Page 218 Causal genes......Page 219 Disease risk......Page 221 FTD: A Heterogeneous Disorder......Page 222 Behavioral and cognitive symptoms......Page 223 Motor symptom management......Page 225 Tau......Page 226 Granulin......Page 231 C9orf72......Page 233 TDP-43......Page 236 Cellular Waste Clearance Systems......Page 237 Heterogeneity = Opportunity......Page 239 Gaps in our Understanding of FTD......Page 241 Toward Early and Targeted Intervention......Page 243 References......Page 244 Huntington’s Disease......Page 268 Huntingtin Gene and Transcripts......Page 270 Huntingtin Protein......Page 274 HD Pathogenic Mechanisms......Page 275 Molecular Strategies for HD......Page 276 ASO......Page 277 RNA Interference......Page 278 Genome Editing......Page 279 Conclusions and Perspectives......Page 280 References......Page 281 Introduction......Page 294 Excitotoxicity......Page 297 Astrocyte Dysfunction......Page 298 Microglial Dysfunction and T Cells......Page 299 Shortage of Neurotrophic Factors......Page 300 Axonal Defects......Page 301 Altered Proteostasis and Autophagy......Page 302 Hexanucleotide Repeats in C9ORF72 and Disturbances in Nucleocytoplasmic Transport......Page 303 Conclusions......Page 304 References......Page 305 Index......Page 314 Back cover......Page 324

Disease-Modifying Targets in Neurodegenerative Disorders: Paving the Way for Disease-Modifying Therapies examines specific neurodegenerative disorders in comprehensive chapters written by experts in the respective fields. Each chapter contains a summary of the disease management field, subsequently elaborating on the molecular mechanisms and promising new targets for disease-modifying therapies.

This overview is ideal for neuroscientists, biomedical researchers, medical doctors, and caregivers, not only providing readers with a summary of the way patients are treated today, but also offering a glance at the future of neurodegenerative disorder treatment.

• Provides a comprehensive overview of how key proteins in neurodegenerative disorders can be used as targets to modify disease progress
• Summarizes how patients are treated today, providing a glance at future disease management
• Includes intelligible and informative information that is perfect for non-specialists, medical practitioners, and scientists
• Written and peer reviewed by outstanding scientists in their respective fields

Disease-Modifying Targets in Neurodegenerative Disorders: Paving the Way for Disease-Modifying Therapies examines specific neurodegenerative disorders in comprehensive chapters written by experts in the respective fields. Each chapter contains a summary of the disease management field, subsequently elaborating on the molecular mechanisms and promising new targets for disease-modifying therapies. This overview is ideal for neuroscientists, biomedical researchers, medical doctors, and caregivers, not only providing readers with a summary of the way patients are treated today, but also offering a glance at the future of neurodegenerative disorder treatment. This book provides a comprehensive overview of how key proteins in neurodegenerative disorders can be used as targets to modify disease progress and summarizes how patients are treated today, providing a glance at future disease management. This book includes intelligible and informative information that is perfect for non-specialists, medical practitioners, and scientists Are you interested in neurosciences? Do you want to understand the molecular basis of neurodegenerative disorders. Do you wonder how we can tackle neurodegeneration today and in the future? Disease-Modifying Targets in Neurodegenerative Disorders provides a comprehensive and state-of-the-art overview of targets, which may pave the way for the development of disease-modifying therapies. Potential therapeutic targets that are common in many neurodegenerative diseases are covered in the first three chapters, followed by a detailed chapter overviews of the most common neurodegenerative disorders, such as Alzheimer's, Parkinson's, Lewy Body Dementia, Frontotemporal Dementia, Huntington's, Amyotrophic Lateral Sclerosis, and Prion disease. Current disease management and the molecular pathogenesis of each disease are carefully summarized, followed by an extensive representation of the most promising targets in the development of a disease-modifying therapy--back cover