Prions and Diseases

Description

Transmissible spongiform encephalopathies (TSE), known as prion diseases, have been recognized for nearly 300 years in animals and almost 100 years in humans. Modern studies, including the protein-misfolding cyclic amplification (PMCA), have greatly advanced our understanding of the pathogenesis of prion diseases and facilitated the identification of new prion diseases in animals and humans. In the second edition of Prions and Diseases, more than 60 leading researchers and clinicians worldwide provide an up-to-date discussion of these unique infectious pathogens and their associated diseases. The book provides up-to-date knowledge about the etiology, pathogenesis, classification, histopathological, and clinical aspects of the full range of animal and human prion diseases. As a result, the book contains by far the most authoritative views about the past, present, and future of prions and prion diseases. The new second edition covers such important emerging topics such as inherited human prion disease, stem-cell models in prion research, human prion disease surveillance, and gene therapy strategies. Preface Contents Part I: History Chapter 1: Transmissible Spongiform Encephalopathy: From Its Beginnings to Daniel Carleton Gajdusek 1.1 In the Beginning … 1.2 Working Out the Biology (in Sheep) 1.3 The Mouse That Roared 1.4 The Nature of the Beast 1.5 The Transition from Biology to Molecular Biology 1.6 The Discovery of Kuru 1.7 The Kuru–CJD–Scrapie Triangle 1.8 Experimental Transmission of Kuru 1.9 The Expanding Horizon of Transmissible Spongiform Encephalopathy 1.10 Clinical and Epidemiological Precisions 1.11 Therapeutic Essays 1.12 The End of an Era References Part II: General Aspects of Prions Chapter 2: The Rich Chemistry of the Copper and Zinc Sites in PrPC 2.1 Introduction 2.2 Brief History 2.3 Features of Cu2+ and Zn2+ Coordination in PrP 2.4 A Role for Altered Copper Coordination in Octarepeat Expansion Disease 2.5 Electrochemical Properties of the PrP Copper Sites 2.6 Copper Regulation of PrPC Proteolytic Cleavage References Chapter 3: PrP Prion Structures 3.1 Introduction 3.2 Development of Initial Parallel In-Register and 4-Rung β-Solenoid Models for PrPSc Fibrils 3.3 Cryo-EM of Synthetic PrP Fibrils 3.4 Near-Atomic Cryo-EM Structures of Infectious Tissue-Derived Prions 3.5 PrPC to PrPSc Conversion 3.6 Impacts of Glycans and GPI Anchors 3.7 Structure-Based Modeling of Transmission Barriers 3.8 Conclusions References Chapter 4: Insoluble Cellular Prion Protein and Other Neurodegeneration-Related Protein Aggregates in the Brain of Asymptomatic Individuals 4.1 Introduction 4.2 Prion Protein Is Characterized by the Presence of an Intrinsically Chameleon-Like Conformation 4.3 Insoluble Cellular Prion Protein Aggregates Are Present in Mammalian Brains Without Prion-Infection 4.4 Spontaneous Formation of the Insoluble Cellular Prion Protein Has Been Modelled with Cultured Cells and May Result from PrP Cytosolic Accumulation 4.5 Physiology and Pathophysiology of Insoluble PrPC Aggregates 4.5.1 Long-Term Memory Storage 4.5.2 Prion Disease 4.5.3 Alzheimer’s Disease 4.6 Insoluble Aβ, Tau, and α-Synuclein Aggregates in the Brain of Asymptomatic Individuals 4.7 Conclusions References Part III: Conversion and Strain of Prions Chapter 5: Prion Conversion and Deformed Templating 5.1 Introduction 5.2 Switching Between Alternative Folding Patterns Within Individual Amyloid Fibrils 5.3 Generating Transmissible Prion Diseases De Novo 5.4 Experimental Evidence Supporting the Mechanism of Deformed Templating 5.5 Deformed Templating In Vivo 5.6 Deformed Templating In Vitro 5.7 Prion Strain Mutation and Evolution via Deformed Templating 5.8 Role of Posttranslational Modifications in Driving Deformed Templating 5.9 Deformed Templating as a Mechanism of a Cross-Talk Between Amyloidogenic Proteins References Chapter 6: Prion Strain Interference 6.1 Introduction 6.2 Parameters Governing Prion Strain Interference 6.2.1 Overview 6.2.2 The Interval Between Prion Strains Inoculation Influences Interference 6.2.3 The Relative Titer of the Blocking and Superinfecting Strains Can Influence Interference 6.2.4 Blocking Strain Replication Is Required for Strain Interference 6.2.5 Infection of Common Neuroanatomical Pathways Is Required for Interference 6.3 Prion Strain Interference and the Replication Site Hypothesis 6.3.1 The Replication Site Hypothesis 6.3.2 The Role of PrPC in Prion Strain Interference 6.3.3 Prion Strain Interactions and Interconversion 6.4 Prion “Vaccination” and Strain Interference References Chapter 7: Molecular Mechanisms Encoding Strains of Prions and Prion-Like Misfolded Proteins 7.1 Prion Diversity 7.2 Distinct Phenotypes of Prion Strains in Bioassay 7.3 Prion Species 7.4 Cell Tropism of Prion Strains 7.5 Conformational Mechanism of Prion Strain Propagation 7.6 Molecular Attributes of Human Prion Strains 7.7 Mechanism of Formation, Replication, and Evolution of Human Prions 7.8 Expanding the Prion Strain Paradigm to Other Age-Related Neurodegenerative Diseases Caused by Protein Misfolding 7.9 Outlook References Chapter 8: Cofactor Involvement in Prion Propagation 8.1 The “Protein-Only” Hypothesis 8.2 Components of Purified Native Prions 8.3 Prion Replication in Cell-Free Conditions 8.4 Formation of Infectious Prions from Minimal Components: Requirement of Non-PrP Cofactor 8.5 The Protein X Hypothesis 8.6 Non-proteinaceous Prion Cofactors 8.7 Potential Roles of Cofactors in Prion Formation and Encoding Infectivity 8.8 Additional Roles and Applications for Prion Cofactors References Chapter 9: Prion Protein Conversion and Lipids 9.1 Introduction 9.2 Supporting Evidence for the Involvement of Lipids in PrP Conversion 9.3 Biophysical Studies of PrP–Lipid Interaction 9.4 Analysis of PrP–Lipid Interaction Using Density Gradient and Protease Digestion 9.5 The Influence of PrP Mutations on rPrP–Lipid Interaction 9.6 Forming Recombinant Prions with Lipid as a Cofactor 9.7 Possible Roles of Lipid in Forming an Infectious Prion References Part IV: Environment and Transmission of Prions Chapter 10: Prions in the Environment 10.1 Introduction 10.2 Prion Sorption to Soil 10.3 Prion Transport in the Environment 10.4 Degradation and Mitigation of Prions in the Environment 10.5 Do Environmental Factors Influence Prion Incidence? 10.6 Detection of Prions in the Environment 10.7 Conclusion References Chapter 11: Environmentally Acquired Transmissible Spongiform Encephalopathy 11.1 Kuru 11.2 Creutzfeldt–Jakob Disease 11.3 Iatrogenic CJD 11.4 The 1970s: Cornea and EEG Depth Electrodes 11.5 The 1980s: Human Growth Hormone (hGH) and Dura Mater Grafts 11.5.1 Human Growth Hormone 11.5.2 Dura Mater 11.6 The 1990s: BSE and vCJD 11.7 The Millennium: Denouement References Chapter 12: Risk of Transmission of Creutzfeldt–Jakob Disease by Blood Transfusion 12.1 Introduction 12.2 Experimental Evidence for Prion Disease Transmission by Blood Transfusion 12.2.1 Cellular Prion Protein in Blood 12.2.2 Animal Models 12.2.3 Rodent Models 12.2.4 Primate Models 12.2.5 Sheep Models 12.3 Evidence for vCJD Transmission by Blood Transfusion and Plasma 12.3.1 Secondary Transmission of vCJD by Blood Transfusion 12.3.2 Evidence for vCJD Transmission by Plasma Products 12.4 Evidence for sCJD Transmission by Blood Transfusion and Plasma 12.5 Methods to Detect Prions in Blood and the Prospect of Implementation of a Blood Screening Test for vCJD 12.5.1 The Challenge 12.5.2 Approaches to Sensitive Detection of PrPSc 12.5.3 PrPSc Amplification and Current Blood Test Development 12.5.4 Future Perspectives 12.6 Conclusion References Chapter 13: Species Barriers in Prion Disease 13.1 Introduction 13.2 Prion Protein and Prion Species Barriers 13.3 Role of PrP Amino Acid Sequence 13.3.1 Region of PrP Involved in Rodent Species Barriers 13.3.2 Influence of Single Amino Acid Residues 13.3.3 Effect of Prnp Heterozygosity 13.4 Influence of PrP Post-translational Modifications 13.4.1 Glycosylation 13.4.2 GPI Anchor 13.5 Non-PrP Host Factors 13.6 Prion Protein Structure and Prion Species Barriers 13.6.1 Structural Regions of PrPC Implicated in Species Barriers 13.6.2 Effect of Variable PrPSc Conformation 13.7 Molecular Model of Prion Species Barriers 13.7.1 Initial Prion Infection and Species Barriers 13.7.2 Prion Adaptation and Species Barriers 13.8 Intermediate Species and Prion Species Barriers 13.8.1 Altered Properties of BSE After Passage into New Species 13.8.2 CWD Host Range and Species Barriers References Part V: Modelling of Prions Chapter 14: Modeling the Cell Biology of Prions 14.1 Cellular Cultures Supporting TSE Agent Replication 14.2 Cell Models of Pathogenic Mutations in the Prion Protein 14.3 Conclusion References Chapter 15: Transgenic Mice Modelling in Prion Diseases 15.1 Introduction 15.2 Host PrP and Susceptibility to TSEs 15.3 Transmission of Agent Within a Host 15.4 Transport into the LRS 15.5 Crossing the Species Barrier and Strain Adaptation 15.6 Defining Strains of TSE Agents 15.7 Mechanisms of Neurodegeneration 15.8 Conclusion References Chapter 16: Stem Cell Models in Prion Research 16.1 Introduction 16.2 Stem Cell Models Used in Prion Research 16.3 Stem Cell Models for Elucidating Prion Cell Biology and Function 16.4 Stem Cell Models for Understanding Normal PrP Function in Progenitors 16.5 Murine Stem Cell Models for Studying Prion Disease 16.6 Human Stem Cell Models of Prion Disease 16.6.1 Infectious Disease 16.6.2 Genetic Disease 16.7 Other Stem Cell Models 16.8 Summary References Chapter 17: Drosophila Models of Prion Diseases 17.1 The Prion Protein in Disease 17.2 Investigating Biological Processes in Animal Models 17.3 Modeling Prion Diseases in Drosophila 17.3.1 Modeling Neurodegeneration in Flies 17.3.2 Early Fly Models of Prion Disease 17.3.3 Modeling Sporadic Prion Diseases: Neurotoxicity of PrP-WT 17.3.4 Physiological Functions PrP 17.3.5 Topological Variants of PrP 17.3.6 PrP Conformational Dynamics: The PrP Zoo 17.3.7 Protective Residues from Resistant Animals 17.3.8 New Drosophila Models Expressing Human PrP 17.3.8.1 Human PrP Exhibits Heightened Toxicity 17.3.8.2 Examining Protective Amino Acids into Human PrP 17.3.9 Genetic Interactions of PrP in Drosophila 17.3.10 Prion Transmission Studies in Flies 17.4 Concluding Remarks References Part VI: Human Prion Diseases and Other Pathologies Chapter 18: Human Sporadic Prion Diseases 18.1 Introduction 18.2 Individual Types and Subtypes 18.3 Mechanisms of Sporadic Prion Disease Heterogeneity: Old and New 18.4 Phenotypic Heterogeneity and Prion Strains 18.5 Concluding Remarks References Chapter 19: Genetics of Prion Disease 19.1 Introduction 19.2 Prion Protein (PrP) 19.3 Molecular Genetics of Prion Disease 19.4 Penetrance 19.5 Other Genes Involved in PrD 19.6 Genetic Prion Disease Subtypes 19.6.1 Creutzfeldt–Jakob Disease (CJD) 19.6.2 Gerstmann–Sträussler–Scheinker Disease (GSS) 19.6.3 Familial Fatal Insomnia (FFI) 19.7 Genotype–Phenotype Correlations 19.8 Transmissibility of Genetic PrD 19.9 PRNP Polymorphisms 19.9.1 Polymorphisms with a Well-Documented Effect on PrD 19.9.2 Polymorphisms with Unclear or No Effect on Disease 19.10 Disease-Associated PRNP Variants 19.11 Octapeptide Repeat Insertions (OPRIs) and Deletions (OPRD) 19.12 Non-OPRI Insertion 19.13 Summary References Chapter 20: Glycoform-Selective Prions in Sporadic and Genetic Variably Protease-Sensitive Prionopathies 20.1 Introduction 20.2 Identification of Sporadic Variably Protease-Sensitive Prionopathy 20.2.1 Dominant PK-Sensitive PrPSc 20.2.2 Unique Multiple Ladder-Like Electrophoretic Gel Profile of PK-Resistant PrPSc 20.2.3 PrP-129 Polymorphism-Dependent Variable PK-Resistant PrPSc 20.2.4 Two Sets of PK-Resistant PrPSc Core Fragments 20.2.5 Glycoform-Selective PrPSc Formation 20.3 Identification of Inherited Variably Protease-Sensitive Prionopathy 20.4 Transmissibility of Sporadic and Genetic VPSPr 20.5 PrPSc Seeding Activity of Sporadic and Inherited VPSPr 20.6 Molecular Origin of PrPSc in Sporadic and Genetic VPSPr 20.7 VPSPr and Other Diseases 20.8 Conclusions References Chapter 21: The Spectrum of Tau Pathology in Human Prion Disease 21.1 Overview of Tauopathies 21.1.1 Classification of Neurodegenerative Diseases 21.1.2 Tau Protein 21.1.3 Classification of Tau-Related Conditions 21.1.4 Immunomorphology of Pathological Tau Deposition in ‘Main’ and ‘Extracellular Filamentous Deposit-RELATED TAUOPAThies’ 21.1.5 Spectrum of Tau Pathology in Other Conditions 21.1.6 How Is Tau Pathology in Prion Diseases to Be Characterized? 21.2 Tau Pathology in Human Prion Diseases 21.2.1 Tau Pathology in Sporadic CJD 21.2.2 Tau Pathology in Acquired CJD 21.2.3 Tau Pathology in Genetic CJD and FFI 21.2.4 Tau Pathology in Dominantly Inherited PrP Cerebral Amyloidoses 21.3 Concluding Remarks 21.3.1 Pathogenesis of Tau Deposition in Human Prion Diseases 21.3.2 Relevance of Tau Protein as Biomarker in Human Prion Diseases 21.3.3 Summary: Classification of Tau Pathology in Human Prion Diseases 21.3.4 Perspectives References Chapter 22: Prion Protein Complex with mGluR5 Mediates Amyloid-ß Synaptic Loss in Alzheimer’s Disease 22.1 Introduction 22.2 Relevant Aβ Species in AD 22.3 Aβo Bind to PrPC 22.4 Therapeutic Strategies Blocking the Aβo-PrPC Interaction 22.5 mGluR5 Facilitates Aβo-PrPC-Induced Toxicity 22.6 Targeting mGluR5 with Allosteric Modulators as Novel Therapy for AD 22.7 Future Outlook References Chapter 23: Prion and Cancers 23.1 Introduction of Prion Protein 23.2 PrP and Cancers 23.2.1 Breast Cancer 23.2.2 Gastric Cancer 23.2.3 Colorectal Cancers 23.2.4 Pancreatic Ductal Carcinoma 23.2.4.1 GPI-PSS Has a Specific Biological Function 23.2.4.2 Filamin A and PrP Binding 23.2.4.3 Expression of pro-PrP Is a Marker of Poorer Prognosis in Pancreatic Cancer 23.2.4.4 Interacting with Nocth1 Signal Transduction Pathway 23.2.5 PrP and Melanoma 23.3 Conclusion and Future Perspective References Chapter 24: Protective Role of Cellular Prion Protein in Tissues Ischemic/Reperfusion Injury 24.1 Introduction 24.2 The Physiological Function of PrPC 24.3 Protective Effect of PrPC on Cerebral Ischemia/Reperfusion Injury 24.4 The Protective Effect of Normal Prion Protein on Cardiac Oxidative Insults 24.5 The Protective Effect of Normal Prion Protein on Renal Ischemia/Reperfusion 24.6 Conclusion References Part VII: Animal Prion Diseases Chapter 25: Bovine Spongiform Encephalopathy 25.1 Introduction 25.2 BSE Epidemics in the UK 25.3 BSE in Europe 25.4 The Impact of the BSE Surveillance System and the Emergence of Atypical BSE Forms 25.5 The Active Surveillance 25.6 The Detection of Atypical BSE Forms by Routine Testing 25.7 Disease Phenotypes of Classical BSE and Atypical Forms of BSE 25.8 Prion Strain Properties in Typical and Atypical BSEs 25.9 On the Origin of BSE 25.10 Cattle BSE and Human Prion Diseases References Chapter 26: Classical and Atypical Scrapie in Sheep and Goats 26.1 Overview 26.2 History 26.3 Geographical Distribution and Surveillance 26.4 Prion Protein Gene and Susceptibility 26.5 Epidemiology of Scrapie 26.5.1 Prevalence in the EU 26.5.2 Transmission Routes in Scrapie 26.5.3 Incubation Period 26.5.4 Pathogenesis and Tissue Distribution of PrPSc and/or Infectivity 26.6 Clinical Signs 26.7 Diagnosis of Scrapie 26.7.1 Discriminatory Immunoblot 26.7.2 Histopathology 26.7.3 Immunohistochemistry 26.8 Scrapie Agent Strains References Chapter 27: Research Models for Studying Chronic Wasting Disease 27.1 Epidemiology 27.2 Pathogenesis 27.3 Transmission 27.4 Effects of Polymorphic Variation in Cervid Prion Protein Genes on Disease Susceptibility 27.5 Transgenic Mouse Models 27.6 Other Transgenic Models 27.7 CWD Strains 27.8 Cell Culture Models for Studying CWD Prions References Part VIII: Yeast Prions Chapter 28: Introduction to Yeast and Fungal Prions 28.1 Mysterious Non-chromosomal Genetic Elements in Yeast 28.2 Discovery of Yeast Prions and the Three Genetic Criteria 28.3 The [Het-s] Prion of Podospora anserina 28.4 The [PIN+] Prion (Rarely) Seeds Other Prions 28.5 [BETA], an Enzyme-Based Prion 28.6 Amyloids as the Basis of Most Yeast Prions 28.7 Chaperones and Other Cellular Factors Affecting Prion Propagation 28.8 Prion Variants and the Species Barrier 28.9 Perspective References Chapter 29: Yeast Prions Are Folded, In-Register Parallel Amyloids Subject to Multiple Anti-prion Systems 29.1 Shuffled Prion Domains of Sup35p or Ure2p Can Still Be Prions 29.2 Solid-State NMR Shows In-Register Parallel Architecture of Yeast Prion Amyloids 29.3 In-Register Parallel Architecture Explains Protein Templating of Conformation 29.4 Biology of Yeast Prions 29.4.1 [Het-s]: Benefit and Detriment 29.4.2 Proposed Benefits of Yeast Prions 29.4.3 Evidence That Yeast Prions Are Diseases 29.5 Anti-prion Systems That Cure Prions in Normal Cells 29.5.1 Btn2 Sequesters Prion Amyloids Promoting Loss by Segregation 29.5.2 Cur1 29.5.3 Proteasomes, Btn2, and Cur1 29.5.4 Hsp104 at Normal Levels Cures Many [PSI+] Prions 29.5.5 Ribosome-Associated Chaperones and [PSI+] 29.5.6 Nonsense-Mediated Decay Proteins (Upf) Have Anti-prion Activity by Complexing with the Prion Protein 29.5.7 Siw14 and Inositol Polyphosphates’ Role in [PSI+] Propagation 29.5.8 Sis1 and Lug1 Limit Toxicity of [PSI+] and [URE3], Respectively 29.6 Perspective References Part IX: Diagnosis and Human Prion Surveillance Chapter 30: Real-Time Quaking-Induced Conversion (QuIC) Assays for the Detection and Diagnosis of Human Prion Diseases 30.1 Introduction 30.2 RT-QuIC 30.3 RT-QuIC for Human Prion Disease Diagnostics 30.4 RT-QuIC for vCJD 30.5 Quantitation by RT-QuIC 30.6 Combining Prion Capture and RT-QuIC 30.7 Technical Considerations 30.8 Biosafety Issues 30.9 Conclusions References Chapter 31: Protein Misfolding Cyclic Amplification 31.1 PMCA: A Great Tool to Study Prion Biology 31.2 PMCA Applications to Understand the Mechanism of Prion Transmission, Species Barrier, and Strain Phenomena 31.3 PMCA Applications in Prion Detection and Diagnosis 31.4 PMCA Applications in the Development of Drugs and Prion Decontamination Procedures 31.5 Expanding PMCA Beyond Prion Diseases 31.6 Concluding Remarks References Chapter 32: Seeding Activity of Skin Misfolded Proteins as a Biomarker in Prion and Prion-Like Diseases 32.1 Introduction 32.2 Infectivity and Seeding Activity of Misfolded Protein Aggregates in Neurodegenerative Diseases 32.3 Association Between the Skin and the Brain 32.4 Skin PrPSc-Seeding Activity in Prion Diseases 32.5 Skin α-Synuclein Seeding Activity in Parkinson’s Disease and Synucleinopathies 32.6 Tau-Seeding Activity in Alzheimer’s Disease and Tauopathies 32.7 Conclusion References Chapter 33: Diagnosis of Prion Disease: Conventional Approaches 33.1 Introduction 33.2 Cerebrospinal Fluid 33.2.1 Routine Tests 33.2.2 14-3-3 Proteins 33.2.3 Tau/p-tau 33.2.4 RT-QuIC 33.2.5 Other CSF Markers 33.2.6 Blood-Based Biomarkers 33.3 Magnetic Resonance Imaging 33.3.1 General Introduction 33.3.2 Test Performance 33.3.3 Changes During the Disease 33.4 EEG 33.5 Molecular Disease Subtype-Specific Diagnosis 33.6 Genetic TSE 33.7 Differential Diagnosis 33.8 Criteria 33.9 Conclusions References Chapter 34: Human Prion Disease Surveillance 34.1 Introduction 34.2 Acquired Human Prion Diseases 34.2.1 Kuru 34.2.2 Iatrogenic Creutzfeldt–Jakob Disease 34.2.3 Variant Creutzfeldt–Jakob Disease 34.3 Methods of Surveillance 34.4 Rationale for Surveillance 34.4.1 Zoonotic Threats 34.4.1.1 Variant Creutzfeldt–Jakob Disease 34.4.1.2 Atypical Bovine Spongiform Encephalopathy 34.4.1.3 Chronic Wasting Disease 34.4.1.4 Camel Prion Disease 34.4.2 Increasing Incidence of Prion Disease Over Time 34.4.3 Investigation of Unrecognized Transmission Routes 34.4.4 Investigation of Disease Clusters 34.4.5 Provide a Research Platform 34.5 Conclusions and Recommendations References Part X: Treatment Chapter 35: Overview on Treatment of Prion Diseases and Decontamination of Prions 35.1 Introduction 35.2 Treatment 35.2.1 Treatment: General Principles 35.2.2 Diagnosis 35.2.3 Disease-Modifying Treatment in Humans 35.2.3.1 The Period Up to 2008 35.2.3.2 Quinacrine 35.2.3.3 Pentosan Polysulphate (PPS) 35.2.3.4 Doxycyline 35.2.3.5 PRN 100 35.2.4 Preventative Treatment in Humans 35.2.5 Treatment: Potential Treatment Targets 35.2.6 Treatment: Identifying Possible Treatments 35.2.7 Treatment: Assessing the Efficacy of Potential Treatments in Humans 35.2.8 Treatment: Assessing the Toxicity of Potential Treatments in Humans 35.2.9 Ethical Considerations 35.3 Decontamination 35.3.1 The Background to Decontamination Concerns 35.3.2 Methods of Decontamination 35.3.3 Assessment of Decontamination Methods References Chapter 36: Gene Therapy Strategies for Prophylactic and Therapeutic Treatments of Human Prion Diseases 36.1 Overview of Human Prion Diseases 36.2 General Strategies for Development of Therapies Against Prion Diseases 36.3 Reported Gene Therapy Tests Against Prion Diseases in Cell or Animals 36.3.1 Reduction of PrPC Levels by RNAi 36.3.2 Inhibition of PrPSc Replication 36.4 Promising Gene Therapy Strategies Against Prion Diseases References Chapter 37: Immunomodulation 37.1 The Immune System and Prion Infection 37.2 In Vitro Studies Using Anti-PrP Antibodies to Block Prion Propagation 37.3 Therapeutic Targeting of Prions: The Challenge of Effectiveness Versus Toxicity 37.4 Passive Immunization for Prion Infection 37.5 Active Vaccination for Prion Infection 37.6 Mucosal Active Immunization 37.7 Conclusions References Index