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.
Table of Contents
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
