Disease-modifying targets in neurodegenerative disorders: paving the way for disease-modifying therapies

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