Metal-Based Neurodegeneration From Molecular Mechanisms to Therapeutic Strategies

Neurodegenerative diseases of the human brain appear in various forms, resulting in disorders of movement and coordination, cognitive deterioration and psychiatric disturbances. Many of the key factors leading to neurodegenerative diseases are similar, including the dysfunction of metal ion homeostasis, redox-active metal ions generating oxidative stress, and intracellular inclusion bodies.

Metal-based Neurodegeneration presents a detailed survey of the molecular origins of neurodegenerative diseases. Each chapter is dedicated to a specific disease, presenting the latest scientific findings,  including details of their biochemical actors (proteins or peptides), their normal and pathological conformations, and a description of the diseases characteristics, with an emphasis on the role of metal-induced oxidative stress, which can result in the production of intracellular aggregates of target proteins and peptides. 

Topics covered include:

• Brain function, physiology and the blood-brain barrier
• Immune system and neuroinflammation
• Aging and mild cognitive impairment, MCI
• Parkinson’s Disease
• Alzheimer’s Disease
• Creutzfelt-Jakob and related prion diseases
• Alcoholic Brain Damage
• Therapeutic strategies to combat the onset and progression of neurological diseases

This extensively updated, full colour, second edition of Metal-based Neurodegeneration is an essential text for research scientists and clinicians working in gerontology, neuropathology, neurochemistry, and metalloprotein mechanisms.

Preface xi

1 Brain Function, Physiology and the Blood–Brain Barrier 1

1.1 Introduction – An Overview of Brain Structure and Function 1

1.1.1 The Forebrain 1

1.1.2 The Midbrain 4

1.1.3 The Hindbrain 4

1.2 The Cell Types of the Brain 7

1.2.1 Neurons 7

1.2.2 Glial Cells 11

1.3 The Blood–Brain Barrier 19

References 21

2 Role of Metal Ions in Brain Function, Metal Transport, Storage and Homoeostasis 23

2.1 Introduction – The Importance of Metal Ions in Brain Function 23

2.2 Sodium, Potassium and Calcium Channels and Pumps 24

2.3 Calcium and Signal Transduction 30

2.4 Zinc, Copper and Iron 37

2.5 Zinc 37

2.6 Copper 41

2.7 Iron 42

References 48

3 Immune System and Neuroinflammation 51

3.1 General Introduction 51

3.1.1 Innate Immune Response and Neuroinflammation 51

3.1.2 Adaptive Immunity and Neuroinflammation 58

3.1.3 Adaptive Immunity and Neuroinflammation 59

3.1.4 Other Factors Contributing to Neuroinflammation 60

3.1.5 Anti-inflammatory Systems to Regulate Microglia Activation 60

3.2 Apoptosis 63

3.2.1 Iron Metabolic Regulators and Effectors during Inflammation 68

References 72

4 Oxidative Stress in Neurodegenerative Diseases 75

4.1 Introduction – The Oxygen Paradox 75

4.2 Reactive Oxygen Species 76

4.3 Reactive Nitrogen Species 79

4.4 Cellular Defence Mechanisms against Oxidative Stress 82

4.5 ROS, RNS and Cellular Signalling 87

4.6 ROS, RNS and Oxidative Damage 91

4.7 Epigenetics 97

4.7.1 Histone Modifications 100

4.8 Misfolded Protein Aggregates in Neurodegenerative Diseases 101

4.9 The Amyloid State – Structure, Nucleation and Aggregation 102

References 107

5 Ageing and Mild Cognitive Impairment (MCI) 111

5.1 Introduction 111

5.1.1 Gene Involvement and Epigenetics 112

5.1.2 DNA Methylation 112

5.1.3 Histone Post-translational Modifications 113

5.2 Prevalence of MCI 114

5.2.1 MCI Presentation 114

5.3 Brain Regions Involved 115

5.3.1 Neurochemical Observations 116

5.3.2 Factors Involved in the Ageing Process 117

5.3.3 Mitochondria and the Ageing Process 117

5.3.4 Free Radical Theory of Ageing 118

5.3.5 Iron, Copper and Zinc in Ageing 119

5.3.6 Risk Factors for Cognitive Decline 121

5.3.7 APOe4 Isoforms and MCI 122

5.3.8 Ageing and Immunity 122

5.4 Proteostasis 126

5.5 Conclusion 127

References 128

6 Parkinson’s Disease 131

6.1 Risk Factors for PD 131

6.2 Genetics of PD 134

6.3 SNCA 135

6.4 LRRK2 135

6.5 Parkin 135

6.6 DJ-1 135

6.7 PINK1: PTEN-Induced Kinase 136

6.8 Epigenetics 136

6.9 miRNA 136

6.10 Proteins Involved in PD 137

6.11 Synucleins 137

6.12 LRRK2 or PARK 8 142

6.13 PINK1 or PTEN-Induced Putative Kinase 1, PARK6 143

6.14 Parkin, PARK2 144

6.15 Synphilin-1 146

6.16 UCHL 1, Park 5 147

6.17 DJ-1, PARK 7 147

6.18 Metal Involvement in Parkinson’s Disease 148

6.18.1 Iron 148

6.18.2 Zinc 153

6.18.3 Copper 154

6.19 Neurotransmitters Involved in PD 154

6.20 Mitochondrial Dysfunction 156

6.21 PD and Inflammation 156

6.22 Receptors Involved in the Inflammatory Response 159

6.22.1 Toll-Like Receptors 159

6.22.2 Glucocorticoid Receptor, GR 159

6.22.3 CD200/CD200R 160

6.22.4 Vitamin D Receptor (VDR) 160

6.22.5 Peroxisome Proliferators-Activated Receptors 161

6.23 Oxidative Stress and PD 161

References 163

7 Alzheimer’s Disease 169

7.1 Introduction 169

7.2 Epidemiology and Risk Factors for AD 171

7.3 Genetics of AD 173

7.3.1 Epigenetics 174

7.4 Proteins Involved in Alzheimer’s Disease 175

7.5 Metal Involvement in Alzheimer’s Disease 179

7.6 Zinc Homoeostasis in AD 181

7.7 Copper Homoeostasis in AD 181

7.8 Iron Homoeostasis in AD 183

7.9 Neurotransmitters Involved in AD 185

7.9.1 Acetyl choline 185

7.9.2 Glutamate 187

7.10 Mitochondrial Function in Alzheimer’s Disease 189

7.11 Neuroinflammation and AD 191

7.12 Oxidative Stress 191

References 195

8 Huntington’s Disease and Polyglutamine Expansion Neurodegenerative Diseases 203

8.1 Introduction 203

8.2 An Overview of Trinucleotide Expansion Diseases 204

8.3 Poly-Q Diseases 204

8.4 Poly-Q Protein Aggregation and Poly-Q Disease Pathogenesis 208

8.5 Huntington’s Disease 211

8.6 Other Poly-Q Disease Proteins 215

8.7 Spinocerebellar Ataxias 218

References 221

9 Friedreich’s Ataxia and Diseases Associated with Expansion of Non-Coding Triplets 227

9.1 Incidence and Pathophysiology of Friedreich’s Ataxia 227

9.2 Molecular Basis of the Disease: Triplet Repeat Expansions 228

9.3 Molecular Basis of the Disease: Frataxin and Its Role in Iron Metabolism 230

9.4 Other Diseases Associated with Expansion of Non-Coding Triplets 233

References 236

10 Creutzfeldt–Jakob and Other Prion Diseases 239

10.1 Introduction 239

10.2 A Brief History of Prion Diseases 240

10.3 Structural Aspects of the Cellular Form of PrPC 241

10.4 ‘Prion’ or ‘Protein-Only’ Hypothesis – Conformation-Based Prion Inheritance 244

10.5 Models of PsPC to PsPSc Conversion 246

10.6 Formation of Prion Aggregates 248

10.7 Pathways of Prion Pathogenesis 253

References 256

11 Amyotrophic Lateral Sclerosis 261

11.1 Introduction 261

11.2 Major Genes Involved in ALS 262

11.3 Superoxide Dismutase and ALS 265

11.4 Contributors to Disease Mechanisms in ALS 269

11.5 Excitotoxicity and Decreased Glutamate Uptake by Astroglia 269

11.6 Endoplasmic Reticulum Stress 270

11.7 Inhibition of the Proteasome 270

11.8 Mitochondrial Damage 271

11.9 Aberrant Secretion of Mutant SOD1 271

11.10 Extracellular Superoxide Generation 271

11.11 Axonal Disorganization and Disrupted Transport 272

11.12 Microhaemorrhages of Spinal Capillaries 272

11.13 Glial Cells in ALS 273

11.14 ALS and Apoptosis 273

11.15 Prion-Like Phenomena in ALS 274

11.16 Conclusions 276

References 276

12 Alcoholic Brain Damage 283

12.1 General Introduction 283

12.2 Anatomy of Alcohol-Induced Damage 285

12.3 Genetics of Alcohol-Induced Brain Damage 286

12.3.1 Epigenetics 286

12.3.2 MicroRNAs 287

12.3.3 Genetics 288

12.4 Factors Associated with Alcohol Brain Damage 291

12.5 Factors Involved in Alcohol-Induced Brain Damage 292

12.5.1 Neuropeptides 292

12.5.2 Neurotransmitters 293

12.5.3 Acetaldehyde 294

12.5.4 Signalling Pathways 295

12.5.5 Neuroinflammation and Alcohol 296

12.5.6 Astrocytes and Alcohol 297

12.5.7 Microglia and Alcohol 300

12.5.8 NF-kB 301

12.5.9 Toll-Like Receptors 302

12.5.10 Oligodendrocytes and Alcohol 303

12.5.11 Alcohol and Mitochondria 303

12.5.12 Alcoholic Brain Damage and Oxidative Stress 304

References 305

13 Other Neurological Diseases 309

13.1 Introduction 309

13.2 Wilson’s and Menkes Diseases 309

13.3 Neurodegeneration with Brain Iron Accumulation 316

13.4 Aceruloplasminaemia 316

13.5 Neuroferritinopathy 318

13.6 Other Neurodegenerative Disorders with Brain Iron Accumulation 320

13.7 Multiple Sclerosis 323

13.8 HIV-Associated Neurocognitive Disorder 329

References 332

14 Therapeutic Strategies to Combat the Onset and Progression of Neurological Diseases 337

14.1 Introduction 337

14.2 Chelation of Excessive Metal Ions 338

14.2.1 Chelation in Parkinson’s Disease 341

14.2.2 Chelation Therapy in AD 341

14.2.3 Chelation in Friedreich Ataxia 343

14.3 Ageing and Cognitive Decline 344

14.3.1 Saturated/Unsaturated Fat Intake 344

14.3.2 Berries 345

14.3.3 Creatine Supplementation 346

14.3.4 Sirtuins 347

14.3.5 Immunity 347

14.3.6 Mitochondria Mutations 348

14.4 Parkinson’s Disease 348

14.4.1 Nutraceutical 349

14.4.2 NASIs and COX2 Inhibitors 351

14.4.3 Physical Exercise 351

14.4.4 Dopamine Agonists 352

14.4.5 Monoamine Oxidase Inhibitors 354

14.4.6 L-DOPA 355

14.4.7 Mitochondria and PD 356

14.4.8 Sirtuins 356

14.4.9 Creatine 357

14.4.10 CoQ10 358

14.4.11 Surgical Treatment for PD 358

14.5 Alzheimer’s Disease 359

14.5.1 Epigenetic Modifications 359

14.5.2 Sirtuins 359

14.5.3 Tau Kinase Inhibitors 359

14.5.4 Neurotransmitters 360

14.5.5 Anti-inflammatory Drugs 360

14.5.6 Strategies to Remove Ab 360

14.5.7 Ab Immunotherapy 363

14.6 Huntington’s Disease and Other Poly-Q Diseases 364

14.7 Friedreich’s Ataxia and Other Non-Coding Nucleotide Repeat Diseases 367

14.8 Creutzfeld–Jakob and Other Prion Diseases 370

14.9 Amyotrophic Lateral Sclerosis 372

14.10 Alcohol Abuse 373

14.11 Other Neurological Diseases 378

14.11.1 Wilson’s and Menkes Diseases 378

14.11.2 Neurodegeneration with Brain Iron Accumulation 379

14.12 Multiple Sclerosis 381

14.13 HIV-Associated Neurocognitive Disorder 386

References 387

15 Concluding Remarks 395

15.1 New Innovative Therapeutics 400

15.1.1 Stem Cells 402

15.2 Biochemical Biomarkers of Neurodegenerative Diseases 404

15.2.1 Parkinson’s Disease 404

15.2.2 Alzheimer’s Disease 404

15.2.3 Alcohol Brain Damage 405

15.2.4 Epilogue 405

References 406

Index

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