Metal-Based Neurodegeneration: From Molecular Mechanisms to Therapeutic Strategies

Metal-based Neurodegeneration: From Molecular Mechanisms to Therapeutic Strategies......Page 1
Contents......Page 7
Preface......Page 13
1.1.1 The Forebrain......Page 17
1.1.3 The Hindbrain......Page 20
1.2.1 Neurons......Page 23
1.2.2 Glial Cells......Page 27
1.3 The Blood–Brain Barrier......Page 35
References......Page 37
2.1 Introduction – The Importance of Metal Ions in Brain Function......Page 39
2.2 Sodium, Potassium and Calcium Channels and Pumps......Page 40
2.3 Calcium and Signal Transduction......Page 46
2.5 Zinc......Page 53
2.6 Copper......Page 57
2.7 Iron......Page 58
References......Page 64
3.1.1 Innate Immune Response and Neuroinflammation......Page 67
3.1.2 Adaptive Immunity......Page 74
3.1.3 Adaptive Immunity and Neuroinflammation......Page 75
3.1.5 Anti-inflammatory Systems to Regulate Microglia Activation......Page 76
3.2 Apoptosis......Page 79
3.2.1 Iron Metabolic Regulators and Effectors during Inflammation......Page 84
References......Page 88
4.1 Introduction – The Oxygen Paradox......Page 91
4.2 Reactive Oxygen Species......Page 92
4.3 Reactive Nitrogen Species......Page 95
4.4 Cellular Defence Mechanisms against Oxidative Stress......Page 98
4.5 ROS, RNS and Cellular Signalling......Page 103
4.6 ROS, RNS and Oxidative Damage......Page 107
4.7 Epigenetics......Page 113
4.7.1 Histone Modifications......Page 115
4.8 Misfolded Protein Aggregates in Neurodegenerative Diseases......Page 117
4.9 The Amyloid State – Structure, Nucleation and Aggregation......Page 118
References......Page 123
5.1 Introduction......Page 127
5.1.2 DNA Methylation......Page 128
5.1.3 Histone Post-translational Modifications......Page 129
5.2.1 MCI Presentation......Page 130
5.3 Brain Regions Involved......Page 131
5.3.1 Neurochemical Observations......Page 132
5.3.3 Mitochondria and the Ageing Process......Page 133
5.3.4 Free Radical Theory of Ageing......Page 134
5.3.5 Iron, Copper and Zinc in Ageing......Page 135
5.3.6 Risk Factors for Cognitive Decline......Page 137
5.3.8 Ageing and Immunity......Page 138
5.4 Proteostasis......Page 142
5.5 Conclusion......Page 143
References......Page 144
6.1 Risk Factors for PD......Page 147
6.2 Genetics of PD......Page 150
6.6 DJ-1......Page 151
6.9 miRNA......Page 152
6.11 Synucleins......Page 153
6.12 LRRK2 or PARK 8......Page 158
6.13 PINK1 or PARK 6......Page 159
6.14 Parkin or PARK 2......Page 160
6.15 Synphilin-1......Page 162
6.17 DJ-1 or PARK 7......Page 163
6.18.1 Iron......Page 164
6.18.2 Zinc......Page 169
6.19 Neurotransmitters Involved in PD......Page 170
6.21 PD and Inflammation......Page 172
6.22.2 Glucocorticoid Receptor, GR......Page 175
6.22.4 Vitamin D Receptor (VDR)......Page 176
6.23 Oxidative Stress and PD......Page 177
References......Page 179
7.1 Introduction......Page 185
7.2 Epidemiology and Risk Factors for AD......Page 187
7.3 Genetics of AD......Page 189
7.3.1 Epigenetics......Page 190
7.4 Proteins Involved in Alzheimer’s Disease......Page 191
7.5 Metal Involvement in Alzheimer’s Disease......Page 195
7.7 Copper Homoeostasis in AD......Page 197
7.8 Iron Homoeostasis in AD......Page 199
7.9.1 Acetylcholine......Page 201
7.9.2 Glutamate......Page 203
7.10 Mitochondrial Function in Alzheimer’s Disease......Page 205
7.12 Oxidative Stress......Page 207
References......Page 211
8.1 Introduction......Page 219
8.3 Poly-Q Diseases......Page 220
8.4 Poly-Q Protein Aggregation and Poly-Q Disease Pathogenesis......Page 223
8.5 Huntington’s Disease......Page 226
8.6 Other Poly-Q Disease Proteins......Page 230
8.7 Spinocerebellar Ataxias......Page 233
References......Page 236
9.1 Incidence and Pathophysiology of Friedreich’s Ataxia......Page 243
9.2 Molecular Basis of the Disease: Triplet Repeat Expansions......Page 244
9.3 Molecular Basis of the Disease: Frataxin and Its Role in Iron Metabolism......Page 246
9.4 Other Diseases Associated with Expansion of Non-Coding Triplets......Page 249
References......Page 252
10.1 Introduction......Page 255
10.2 A Brief History of Prion Diseases......Page 256
10.3 Structural Aspects of the Cellular Form of PrPC......Page 257
10.4 ‘Prion’ or ‘Protein-Only’ Hypothesis – Conformation-Based Prion Inheritance......Page 260
10.5 Models of PsPC to PsPSc Conversion......Page 262
10.6 Formation of Prion Aggregates......Page 264
10.7 Pathways of Prion Pathogenesis......Page 269
References......Page 272
11.1 Introduction......Page 277
11.2 Major Genes Involved in ALS......Page 278
11.3 Superoxide Dismutase and ALS......Page 281
11.5 Excitotoxicity and Decreased Glutamate Uptake by Astroglia......Page 285
11.7 Inhibition of the Proteasome......Page 286
11.10 Extracellular Superoxide Generation......Page 287
11.12 Microhaemorrhages of Spinal Capillaries......Page 288
11.14 ALS and Apoptosis......Page 289
11.15 Prion-Like Phenomena in ALS......Page 290
References......Page 292
12.1 General Introduction......Page 299
12.2 Anatomy of Alcohol-Induced Damage......Page 301
12.3.1 Epigenetics......Page 302
12.3.2 MicroRNAs......Page 303
12.3.3 Genetics......Page 304
12.4 Factors Associated with Alcohol Brain Damage......Page 307
12.5.1 Neuropeptides......Page 308
12.5.2 Neurotransmitters......Page 309
12.5.3 Acetaldehyde......Page 310
12.5.4 Signalling Pathways......Page 311
12.5.5 Neuroinflammation and Alcohol......Page 312
12.5.6 Astrocytes and Alcohol......Page 313
12.5.7 Microglia and Alcohol......Page 316
12.5.8 NF-kB......Page 317
12.5.9 Toll-Like Receptors......Page 318
12.5.11 Alcohol and Mitochondria......Page 319
12.5.12 Alcoholic Brain Damage and Oxidative Stress......Page 320
References......Page 321
13.2 Wilson’s and Menkes Diseases......Page 325
13.4 Aceruloplasminaemia......Page 332
13.5 Neuroferritinopathy......Page 334
13.6 Other Neurodegenerative Disorders with Brain Iron Accumulation......Page 336
13.7 Multiple Sclerosis......Page 339
13.8 HIV-Associated Neurocognitive Disorder......Page 345
References......Page 348
14.1 Introduction......Page 353
14.2 Chelation of Excessive Metal Ions......Page 354
14.2.2 Chelation Therapy in AD......Page 357
14.2.3 Chelation in Friedreich Ataxia......Page 359
14.3.1 Saturated/Unsaturated Fat Intake......Page 360
14.3.2 Berries......Page 361
14.3.3 Creatine Supplementation......Page 362
14.3.5 Immunity......Page 363
14.4 Parkinson’s Disease......Page 364
14.4.1 Nutraceutical......Page 365
14.4.3 Physical Exercise......Page 367
14.4.4 Dopamine Agonists......Page 368
14.4.5 Monoamine Oxidase Inhibitors......Page 370
14.4.6 L-DOPA......Page 371
14.4.8 Sirtuins......Page 372
14.4.9 Creatine......Page 373
14.4.11 Surgical Treatment for PD......Page 374
14.5.3 Tau Kinase Inhibitors......Page 375
14.5.6 Strategies to Remove Aβ......Page 376
14.5.7 Aβ Immunotherapy......Page 379
14.6 Huntington’s Disease and Other Poly-Q Diseases......Page 380
14.7 Friedreich’s Ataxia and Other Non-Coding Nucleotide Repeat Diseases......Page 383
14.8 Creutzfeld–Jakob and Other Prion Diseases......Page 386
14.9 Amyotrophic Lateral Sclerosis......Page 388
14.10 Alcohol Abuse......Page 389
14.11.1 Wilson’s and Menkes Diseases......Page 394
14.11.2 Neurodegeneration with Brain Iron Accumulation......Page 395
14.12 Multiple Sclerosis......Page 397
14.13 HIV-Associated Neurocognitive Disorder......Page 402
References......Page 403
15 Concluding Remarks......Page 411
15.1 New Innovative Therapeutics......Page 416
15.1.1 Stem Cells......Page 418
15.2.2 Alzheimer’s Disease......Page 420
15.2.4 Epilogue......Page 421
References......Page 422
Index......Page 425